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Molecular mechanism to target the endosomal Mon1-Ccz1 GEF complex to the pre-autophagosomal structure

  1. Jieqiong Gao
  2. Lars Langemeyer
  3. Daniel Kümmel
  4. Fulvio Reggiori
  5. Christian Ungermann  Is a corresponding author
  1. University of Osnabrück, Germany
  2. University Medical Center Groningen, University of Groningen, Netherlands
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Cite as: eLife 2018;7:e31145 doi: 10.7554/eLife.31145

Abstract

During autophagy, a newly formed double membrane surrounds its cargo to generate the so-called autophagosome, which then fuses with a lysosome after closure. Previous work implicated that endosomal Rab7/Ypt7 associates to autophagosomes prior to their fusion with lysosomes. Here, we unravel how the Mon1-Ccz1 guanosine exchange factor (GEF) acting upstream of Ypt7 is specifically recruited to the pre-autophagosomal structure under starvation conditions. We find that Mon1-Ccz1 directly binds to Atg8, the yeast homolog of the members of the mammalian LC3 protein family. This requires at least one LIR motif in the Ccz1 C-terminus, which is essential for autophagy but not for endosomal transport. In agreement, only wild-type, but not LIR-mutated Mon1-Ccz1 promotes Atg8-dependent activation of Ypt7. Our data reveal how GEF targeting can specify the fate of a newly formed organelle and provide new insights into the regulation of autophagosome-lysosome fusion.

https://doi.org/10.7554/eLife.31145.001

eLife digest

Autophagy is a word derived from the Greek for “self-eating”. It describes a biological process in which a living cell breaks down its own material to release their chemical building blocks that can then be used to make new molecules. Autophagy is often triggered when a cell becomes damaged or when nutrients are in short supply. The hallmark of autophagy is the formation of structures called autophagosomes. These structures capture the cellular material, fuse with other compartments in the cell – namely endosomes in animals and vacuoles in yeast – and then deliver the material inside, ready to be broken down.

For an autophagosome to fuse to an endosome or a vacuole, small proteins of the Rab protein family must be located on the surface of the autophagosome. Rab proteins are recruited to this surface by enzymes known as GEFs. However it remains unclear how most GEFs get to the surface of a compartment within the cell to begin with.

The Mon1-Ccz1 complex is a GEF that occurs in yeast and animals, including fruit flies and humans. It is found on endosomes, and was recently shown to also localize to autophagosomes. Now, Gao et al. report that, in yeast, the Mon1-Ccz1 complex binds directly to a protein named Atg8. This protein is anchored on to the surface of autophagosomes, and is closely related to other proteins in animal cells.

Gao et al. discovered that this specific GEF binds to Atg8 via at least one binding site on its Ccz1 component. This binding site is only needed for the GEF to localize to the autophagosomes; the Mon1-Czz1 complex can still bind to endosomes without it. Blocking the GEF from binding to Atg8 stopped the autophagosomes from fusing with vacuoles.

These findings reveal how a GEF can be targeted to two distinct compartments in the cell: endosomes and autophagosomes. Further work is now needed to understand how this process is regulated by the availability of nutrients or damage to the cell, to ensure that autophagy is only triggered under the right conditions. Also, because cancer cells often rely on autophagy to survive, the molecules that regulate this process could represent possible targets for new anticancer drugs.

https://doi.org/10.7554/eLife.31145.002

Introduction

Macroautophagy, called here autophagy, is an important quality control pathway, during which cellular material such as organelles and cytosolic components are engulfed by a double-membrane vesicles, the autophagosome (Shibutani and Yoshimori, 2014; Mizushima et al., 2011). In both yeast and mammals, autophagosome formation is a complex process that begins with the assembly of the phagophore or isolation membrane. Once complete, the autophagosome first fuses with endosomes to form an amphisome and then with lysosomes in mammalian cells, while it directly fuse with the lysosome-like vacuole in yeast (Lamb et al., 2013; Chen and Klionsky, 2011).

How autophagosomes become fusion competent with lysosomes is still poorly understood. Like for other fusion events, autophagosome fusion with vacuoles or endosomes requires SNAREs, Rab GTPases (Rabs) and the HOPS tethering complex (Reggiori and Ungermann, 2017; Barr, 2013; Kümmel and Ungermann, 2014). Rabs have a central role in this fusion cascade. They are held soluble in the cytosol by the GDP-dissociation inhibitor (GDI) proteins, which bind GDP-loaded Rabs. Once on membranes, a Rab-specific guanine nucleotide exchange factor (GEF) converts Rabs into their active GTP-form (Barr, 2013). This allows their interaction with effectors such as tethering factors (Kümmel and Ungermann, 2014). The Rab7 GTPase is required for the fusion of endosomes with lysosomes and lysosomal transport (Nordmann et al., 2012). In yeast, the Rab7-homolog Ypt7 binds to the HOPS tethering complex in this process, which in turn supports SNARE assembly and fusion. Rab7 as well as Ypt7 are also required for fusion of autophagosomes with endosomes (Gutierrez et al., 2004; Ganley et al., 2011; McEwan et al., 2015) and detected on autophagosomes (Hegedűs et al., 2016).

The conserved Mon1-Ccz1 GEF complex triggers endosomal maturation by activating Ypt7 (or Rab7 in metazoans) primarily on late endosomes (Nordmann et al., 2010; Gerondopoulos et al., 2012; Singh et al., 2014; Cui et al., 2014), but likely also on autophagosomes (Hegedűs et al., 2016). In agreement with this notion, it has been shown that yeast Mon1-Ccz1 is essential for autophagy progression (Wang et al., 2002). As Mon1-Ccz1 can interact with Rab5-GTP, Rab5 may promote Rab7 recruitment to endosomes, possibly with support by the local generation of phosphatidylinositol-3-phosphate (PI-3-P) (Singh et al., 2014; Hegedűs et al., 2016; Cui et al., 2014). It remains unresolved, however, how Mon1-Ccz1 is specifically targeted to autophagosomes to trigger SNARE-mediated fusion (Figure 1A). The SNAREs involved in this event have been implicated in previous studies (Darsow et al., 1997; Fischer von Mollard and Stevens, 1999; Dilcher et al., 2001; Sato et al., 1998; Reggiori and Ungermann, 2017).

Figure 1 with 2 supplements see all
Mon1-Ccz1 and Ypt7 localize to autophagosomes during starvation.

(A) Working model of autophagosome-vacuole fusion. Red lines indicate the involved SNAREs Vam3, Vam7, Vti1, and Ykt6. Ypt7 is shown bound to the HOPS complex. For details see text. (B–H) Localization of Atg8 relative to Ccz1 and Ypt7 during growth and nitrogen starvation. Cells expressing mCherry-tagged Atg8 or GFP-tagged Ccz1 or Ypt7 were grown in YPD (normal, +N) or in synthetic medium without nitrogen (SD-N, labeled as N-starved) for 2 hr and analyzed by fluorescence microscopy and showed via individual slices. Size bar, 5 µm. (F–I) Percentage of Ccz1 puncta (F) or Ypt7 puncta (I) co-localizing with Atg8 under both conditions. Atg8 dots (n ≥ 50), Ccz1 dots (n ≥ 300) and Ypt7 dots (n ≥ 200) were quantified by Image J. Error bars represent standard deviation (SD). (K) Relocalization of Ccz1 during starvation. Time course of mCherry-tagged Vps21 and Atg8 relative to GFP-tagged Ccz1. Error bars represent SD.

https://doi.org/10.7554/eLife.31145.003

Atg8 is one of 16 conserved autophagy-related (Atg) proteins, which are essential for autophagosome formation, and it possesses six mammalian homologues (Shpilka et al., 2012). Members of the Atg8/LC3 protein family are conjugated to phosphatidylethanolamine (PE) at the autophagosome membrane, and interact with several Atg proteins via a LC3 interacting region (LIR motif) to control both maturation and fusion (Wild et al., 2014; Nakatogawa et al., 2007; Klionsky and Schulman, 2014; Abreu et al., 2017). Here, we demonstrate that Atg8 recruits the endosomal GEF Mon1-Ccz1 to the pre-autophagosomal structure. Mutants in a LIR motif present in the Ccz1 C-terminal do not impair GEF activity or endosomal function, but block autophagosome fusion with vacuoles. Our data thus reveal how a GEF can mark two different organelles with the same Rab for fusion via distinct mechanisms.

Results

To determine how yeast autophagosomes are specifically decorated with Ypt7, we analyzed the subcellular distribution of both Mon1 and Ccz1 as the GEF complex formed by these two proteins (Nordmann et al., 2010). In particular, we co-localize GFP-tagged Mon1 and Ccz1 with mCherry-tagged Atg8, an autophagosome marker protein (Suzuki et al., 2007), in wild type cells in growing and nitrogen starvation conditions, which induce autophagy. In yeast, autophagosomes form at the pre-autophagosomal assembly site proximal to the ER and vacuole, which is visible as a single dot-like structure by fluorescence microscopy (Klionsky et al., 2016; Graef et al., 2013; Suzuki et al., 2013; Mari and Reggiori, 2010). Ccz1 and Mon1 were found in distinct puncta, likely endosomes (Rana et al., 2015; Nordmann et al., 2010), which were not co-localizing with the Atg8 puncta in nutrient-rich conditions (Figure 1B; Figure 1—figure supplement 1A). After nitrogen starvation, however, Atg8 labeled the vacuole lumen in wild-type cells as expected (Rieter et al., 2013). This made it impossible to localize Ccz1 or Mon1 to autophagosomes under these conditions, because of their rapid fusion with the vacuole upon completion (Geng et al., 2008). We therefore employed different strategies to block fusion of autophagosomes with vacuoles to determine whether Ypt7, Ccz1, and Mon1 transiently co-localize with Atg8. Deletion of the vacuolar Qa-SNARE Vam3, or temperature sensitive mutants of either Vam3 or the HOPS subunit Vps11 block fusion processes with the vacuole (Darsow et al., 1997; Peterson and Emr, 2001). When cells with these mutations were starved, we indeed observed an accumulation of Atg8-positive autophagosomes, and both Ccz1 and Mon1 were markedly co-localizing with them (Figure 1C–E, quantified in F; Figure 1—figure supplement 1B,C). Likewise, a fraction of Ypt7 colocalized with Atg8 in vam3∆ cells only during starvation (Figure 1G–I). In agreement with this, purified autophagosomes contained both Ypt7 and Mon1-Ccz1 on their surface (Gao and Ungermann, in preparation). Furthermore, we analyzed GFP-Ypt7 in cells overexpressing Ape1. Ape1 overexpression results in the formation of a giant Ape1 oligomer, which is too large to be closed by the isolation membrane marked by mCherry-Atg8 (Suzuki et al., 2013). We found that Ypt7 localizes on the cup-shaped isolation membrane concentrated in a dot in wild-type and vam3∆ cells (Figure 1—figure supplement 1). These data support our interpretation that Ypt7 is present on the autophagosomal membrane. To determine whether starvation promotes the redistribution of Ccz1 to autophagosomes relative to endosomes, we monitored Ccz1 co-localization with Atg8 or Vps21, an endosomal marker protein (Cabrera et al., 2013), over time. Indeed, the fraction of Ccz1 in Vps21-positive organelles decreased, while the localization to Atg8-positive puncta increased during the monitored time period (Figure 1K). As recently published (Zhou et al., 2017), we found the vps21∆ mutant displays impaired autophagy as monitored by the processing of initially cytosolic Pho8∆60 in the vacuole lumen (Figure 1—figure supplement 2E). We also noticed that Ccz1 is cytosolic in vps21∆ cells before and after starvation, which did not allow us to detect this protein on autophagosomal structures (Figure 1—figure supplement 2A–D). It is possible that the localization of Mon1-Ccz1 to endosomes is a prerequisite for a later the movement of the GEF complex to autophagosomes during starvation.

These data suggest that the Mon1-Ccz1 complex is specifically recruited to autophagosomes. To monitor the potential contribution of Atg proteins, including Atg8, in targeting Mon1-Ccz1 and Ypt7 to autophagosomes, we selected the precursor Ape1 oligomer (Kim et al., 1997), a specific autophagosomal cargo behaving similar to Atg8 under starvation conditions, for a small colocalization screen. In wild-type cells and in agreement with the data obtained using mCherry-Atg8 (Figure 1B,G; Figure 1—figure supplement 1A), the starvation-induced co-localization with Ape1 was observed for Ypt7 but not for Ccz1 (Figure 2A,B; Figure 2—figure supplements 1 and 2). To clarify the contribution of known Atg proteins in this process, we generated double knock out mutants lacking VAM3 and selected ATG genes and repeated the assay. In vam3atg1∆ cells as in vam3∆ cells Ccz1 and Ypt7 both robustly colocalized with Ape1 upon nutrient deprivation (Figure 2A,B; Figure 2—figure supplements 1 and 2). However, all the mutants blocking Atg8 conjugation to PE such as those lacking the components of the conjugation machinery or Atg8 itself, abolished colocalization of Ccz1 and Ypt7 with Ape1. Interestingly, the deletion of Atg14, a subunit of the PI-3-kinase I complex required for autophagy (Kihara et al., 2001), did not impair colocalization of Ccz1 and Ape1 on autophagosomes (Figure 2A; Figure 2—figure supplement 1), though affected Ypt7 colocalization with Ape1 (Figure 2B; Figure 2—figure supplement 2). Colocalization of Ape1 relative to Atg8 was not affected in the atg14 mutant (Figure 2—figure supplement 2). This suggests that PI-3-P is not a main determinant for Mon1-Ccz1 targeting to autophagosomes, though might support its activity and/or recruitment of Ypt7.

Figure 2 with 3 supplements see all
Atg8 binds to Mon1-Ccz1 via the Ccz1 C-terminal part.

(A–B) Atg8 is required for localization of Ccz1 to autophagosomes. Graphs show percentage of colocalization of Ccz1 puncta (A) or Ypt7 puncta (B) relative to Ape1 puncta in wild-type and the different mutants. Cells were grown and analyzed as in Figure 1. Ape1 dots (n ≥ 50), Ccz1 dots (n ≥ 300), and Ypt7 dots (n ≥ 200) were quantified by Image J. Error bars represent SD. (C–E) Interaction analysis of Atg8 with Mon1-Ccz1. (C) Immunoprecipitation of TAP-tagged Ccz1 from wild-type and atg4∆ strain co-expressing GFP-Atg8. The strain was grown in YPD or in SD-N for 3 hr before preparing cell extracts. GFP-Atg8 was subsequently immunoprecipitated using GFP-trap beads. Finally, immunoprecipitates were analyzed by Western blotting against GFP and CbP-tag. The graph is the quantification of three independent experiments, where the interaction observed in unstarved cells from wild-type is set as 1. Error bars are SD. (D) Interaction of Atg8 with Mon1-Ccz1 or purified Ccz1. TAP-tagged proteins (shown as purified proteins on Coomassie stained gels to left) were incubated with GST, GST-ubiquitin, and GST-Atg8 immobilized on GSH-Sepharose. Eluted proteins were resolved by SDS-PAGE and analyzed by Western blotting against the CbP-tag (top) or by Coomassie staining (bottom). Load, 10%. (E) Interaction of Atg8 mutants with Mon1-Ccz1. Analysis was done as in (D) with the indicated GST-tagged Atg8 truncation mutants. (F) Interaction of Mon1-Ccz1∆C with Atg8. Mon1-Ccz1∆C was purified as wild-type and analyzed for interaction with GST-tagged Atg8 as before. Top, Western blot against the CbP tag. A star indicates the additional decoration of GST-Atg8 by the antibody; bottom, Coomassie staining and quantification of three experiments. (G) Requirements of Mon1 and Ccz1 domains for autophagy. The indicated truncations were analyzed in cells expressing mCherry-tagged Atg8. Vacuoles were stained with CMAC, and cells grown in SD-N medium were then analyzed by fluorescence microscopy as in Figure 1B. Size bar, 5 µm.

https://doi.org/10.7554/eLife.31145.009

Taken together these observations indicate that Mon1-Ccz1 recruitment onto autophagosome requires Atg8. To determine whether Mon1-Ccz1 binds to Atg8 in vivo, we immunoprecipitated GFP-tagged Atg8 from wild-type and atg4∆ cells co-expressing Ccz1-TAP. Atg4 is required for processing of Atg8 prior to its lipidation on the preautophagosomal structure (Chen and Klionsky, 2011). In agreement with our previous finding, we observed an interaction of Ccz1 with Atg8 in wild-type cells, which was greatly enhanced when cells were starved prior to lysis. In contrast, no interaction was observed in atg4∆, supporting our notion that Ccz1 binds to lipidated Atg8 on autophagosomal structures in vivo (Figure 2C). We next investigated whether Mon1-Ccz1 could bind to Atg8 directly. We thus incubated purified Mon1-Ccz1 with immobilized GST-Atg8 or ubiquitin, and detected robust binding only to Atg8 (Figure 2D). Atg8 recognizes LIR motifs via its N-terminal helices (Klionsky and Schulman, 2014). We therefore tested if truncation mutants of Atg8 lacking the 8 or 24 N-terminal residues still bind Mon1-Ccz1. Importantly, binding was now lost strongly suggesting that Mon1-Ccz1 specific association to Atg8 is mediated by one or more LIR motifs (Figure 2E). To further test whether this interaction depends on the Ccz1 LIR motif(s), we generated an Atg8 I21R mutant, which blocks the binding pocket for the crucial W0 LIR motif residue (Noda et al., 2008). We observed no binding between Atg8 I21R and Ccz1 (Figure 2E), indicating that Atg8 indeed recognizes a LIR motif in Ccz1. This Atg8 mutant functions in non-selective autophagy (Figure 2—figure supplement 3A–C), yet has some defect in selective autophagy when we followed ApeI processing during starvation (Figure 2—figure supplement 3D). It thus behaves like previously characterized mutants at this site (Noda et al., 2008).

We then asked which part of Mon1-Ccz1 binds to Atg8. Mon1 and Ccz1 interact with each other via their conserved longin domains (Nordmann et al., 2010; Cabrera et al., 2014), which form a common interface that is required for specific Ypt7 activation (Kiontke et al., 2017). However, Mon1 has some additional 150 residues at the N-terminus of its longin domain, and both Mon1 and Ccz1 have C-terminal domains, whose structure and function is so far unresolved. We therefore generated N- and C-terminal truncation mutants of both proteins and monitored localization and autophagy. In starvation conditions, GFP-tagged truncation mutants of Mon1 expressed in the mon1∆ background did not impair vacuole morphology or starvation-induced Atg8 trafficking to the vacuole lumen (Figure 2G). We noted though that GFP-Mon1 localization was more strongly impaired in the N-terminal than the C-terminal truncation. In contrast, deletion of the C-terminal domain of GFP-tagged Ccz1 resulted in fragmented vacuoles, even though Ccz1 was still localized to distinct puncta that did not co-localize with Atg8 (Figure 2G). We thus asked whether Ccz1 alone might be able to directly interact with purified Atg8. Although purified Mon1-Ccz1 as well as Ccz1 alone were able to bind GST-Atg8 (Figure 2D), a mutant complex of Mon1 with Ccz1∆C showed strongly reduced interaction (Figure 2F). Altogether, these observations suggest that the C-terminal part of Ccz1 directs the GEF complex to Atg8-positive autophagosomes.

Identification of putative LIR motifs in Ccz1

To determine the direct binding site in the Ccz1 C-terminal, we compared the C-termini of multiple Ccz1 homologs. As metazoan Ccz1 is shorter than yeast Ccz1, we narrowed our search on the conserved fragment and identified the putative LIR motifs (https://ilir.warwick.ac.uk; Figure 3A). We generated the corresponding mutants by changing the aromatic W0 and the hydrophobic L4 residues into alanines. Among the nine mutants (Figure 3A), two showed impaired GFP-Ccz1 localization to mCherry-Atg8-positive autophagosomes under nitrogen starvation conditions, that is Y236A V239A (named LIR1) and Y445A L448A (LIR2) (Figure 3B,C,E). These two motifs are highly conserved across species (Figure 3B). However, we noticed that trafficking of mCherry-tagged Atg8 to the vacuole was not totally compromised in the single mutants at normal growth temperature (Figure 3C). We therefore combined both mutations and nitrogen starved the cells. This resulted in a complete block of autophagy in the double mutant as shown by defects in Atg8 delivery and processing in the vacuole (Figure 3C and F), but also vacuole morphology (Figures 3C and 4D). Under these conditions, numerous mCherry-Atg8-positive autophagosomes accumulated in the cytoplasm, consistent with a defect in fusion with vacuoles. The LIR1,2 mutant behaves thus as the Ccz1∆C mutant, and is likewise compromised in both autophagy and vacuole biogenesis in general (Figures 2F and 3C,F).

Identification of the LIR motifs in Ccz1 required for function.

(A) Schematic representation of potential LIR motifs of the C-terminal part of Ccz1. Blue and red indicates all LIR motifs analyzed, red the motifs that also impair Ccz1 localization. (B) Alignments of the potential Ccz1 LIR motifs Mm: Mus musculus, Hs: Homo sapiens, Cg: Candida glabrata, Lt: Lachancea thermotolerans, Nd: Naumovozyma dairenensis, Ka: Kazachstania Africana. (C–D) Effect of LIR mutants on localization, autophagy and vacuole morphology. Analysis was done as in Figure 1B–H. CMAC staining was done for 15 min before analysis. Cells were grown either at 30°C or 37°C during growth or starvation. Size bar, 5 µm. (E) Quantification of Atg8 dots per cell from images in (C–D). Error bars represent SD. (F) Analysis of autophagy over time. Cells were grown at 30°C and incubated in starvation medium for the indicated time periods, then harvested, and proteins were analyzed by SDS-PAGE and Western blotting against GFP.

https://doi.org/10.7554/eLife.31145.017
LIR motifs in Ccz1 are required for Atg8 binding, but not for the endocytic pathway.

(A–C) Interaction of Ccz1 LIR mutants with Atg8. (A) Analysis of purified Mon1-Ccz1 wild-type and mutant complex by SDS-PAGE and Coomassie staining. All of strains were grown at 30°C for purification. (B–C) Mutations in the LIR motifs impair Mon1-Ccz1 interaction with Atg8. Interaction analysis was done as in Figure 2D, and proteins were analyzed by Western blotting (top) and Coomassie staining (bottom). (D) Comparison of vacuole morphology in LIR mutant cells. Cells were grown at 30 or 37°C in starvation medium, and vacuoles were then stained with CMAC. The number of vacuoles per cell was quantified as indicated. Error bars, SD. (E) Effect of LIR mutants on sorting of vacuolar hydrolases. The indicated cells were grown in starvation medium at the indicated temperature for 2 hr. Total cell lysates were generated and proteins were resolved on SDS-PAGE. Western blots were decorated against CPY and Tom40 (as loading control). (F) Endocytosis analysis in LIR mutants. The indicated cells expressing Mup1-GFP were grown in the absence (-Met) of methionine in minimal medium to an OD600 of 1.0 at the 23°C. Where indicated, methionine was added after the temperature shift to 37°C, and cells were analyzed by fluorescence microscopy after 1 hr. Size bar, 5 µm.

https://doi.org/10.7554/eLife.31145.019

We therefore focused on the single mutants. We were wondering why the single LIR mutants were still functional, even though Ccz1 targeting seemed diminished. We considered the possibility that the LIR mutants may be impaired at higher temperature, and thus repeated the starvation assay at 37°C (Figure 3D). Although the wild-type cells were functional in autophagy, both LIR mutants now accumulated Atg8-positive autophagosomes in cells (Figure 3D, quantified in E).

To test if these LIR mutants indeed compromise binding to Atg8, we produced and used the mutants in Atg8 binding assays (see Figure 2D–F). Both LIR1 and the LIR1,2 double mutants could be purified as wild-type Mon1-Ccz1 from yeast, indicating that they were not destabilizing the complex (Figure 4A). However, they showed poor interaction with Atg8 (Figure 4B,C). As we encounter major problems in the purification of the Mon1-Ccz1 complex with LIR2, we did not further pursue it in our in vitro analyses. Nonetheless, these data agree with a model, where one and possibly two Ccz1 LIR motifs are required for the recruitment of Mon1-Ccz1 to Atg8.

The Ccz1 LIR motifs are not required for endosomal trafficking

Our data suggest an important function of the one and possibly two LIR motifs in directing Mon1-Ccz1 to autophagosomes. As vacuole morphology of the LIR1 and LIR2 mutants was only mildly impaired during heat stress (Figures 3D and 4D), we asked if endosomal trafficking was functional in these mutants. The vacuolar hydrolase carboxypeptidase Y (CPY), which is normally sorted from the Golgi via the endosome to the vacuole, is lost from cells in mutants impaired in vacuole biogenesis such as vps39∆ or the temperature sensitive mutant vps11-1 at 37°C (Figure 4E). Likewise, ccz1∆ cells have less intracellular CPY. However, both LIR mutants in Ccz1 were entirely unperturbed also at elevated temperature or when cells were starved. As a second assay, we traced the sorting of the methionine transporter Mup1 from the plasma membrane to the vacuole (Arlt et al., 2015). In both wild-type cells and the LIR mutants, Mup1-GFP was mainly at the plasma membrane in the absence of methionine, but was efficiently sorted to the vacuole lumen when methionine was added after the temperature shift to 37°C (Figure 4F). This sorting remained unaffected at higher temperatures as well. We therefore conclude that the LIR1 and LIR2 mutants selectively disable Mon1-Ccz1 targeting to autophagosomes, whereas endosomal function of Mon1-Ccz1 remains unperturbed under the same conditions.

Atg8 specifies Mon1-Ccz1 function on autophagosomal membranes

Our data imply that Atg8 is indeed a primary determinant to recruit Mon1-Ccz1 to autophagosomes. We used our Mon1-Ccz1 LIR1 mutant to directly test this hypothesis as this was the best behaving complex. From previous in vitro experiments with purified organelles and proteins we have learned that mutations can compromise protein function in vitro much more clearly than in vivo (Bröcker et al., 2012; Ungermann et al., 1999). We therefore took advantage of GEF assay that we developed before to monitor Mon1-Ccz1 activity on membrane-bound Ypt7 (Cabrera et al., 2014). C-terminally His-tagged Ypt7 was preloaded with the MANT-GDP nucleotide, which looses fluorescence when exchanged for non-fluorescent GTP. In the presence of liposomes carrying the His-interacting DOGS-NTA lipid, and the nucleotide exchange reaction is strongly enhanced when Mon1-Ccz1 is also recruited onto the liposome surface (Cabrera et al., 2014). Using this assay, we compared wild-type and LIR1 mutated Mon1-Ccz1 complex (Figure 5A). Both complexes had similar activity for Ypt7 (Figure 5A,D). We then lowered the Mon1-Ccz1 concentration in our assay to test whether Mon1-Ccz1 targeting and function could depend on membrane-bound Atg8. Indeed, membrane-targeted Atg8-His, but not soluble Atg8, stimulated the GTP exchange reaction (Figure 5B,D), presumably due to its ability to recruit the GEF complex to membranes. In contrast, the Mon1-Ccz1 LIR mutant did not respond to the addition of Atg8 (Figure 5C,D). Our data thus show that membrane-bound Atg8 can recruit Mon1-Ccz1 to membranes to promote Ypt7 activation.

Functional reconstitution of Atg8-dependent GEF activity of Mon1-Ccz1.

(A) GEF activity of wild-type and mutant Mon1-Ccz1 complex. GEF activity was monitored by displacement of MANT-GDP from Ypt7 using a microplate reader (see Materials and methods). Assay was carried out with liposomes capable of binding His-tagged Ypt7 (Cabrera et al., 2014). Without GTP, blue line; without GEF, black line; wt refers to different concentrations of Mon1-Ccz1, LIR1 to the Mon1-Ccz1 mutant complex. (B–D) Effect of membrane-bound Atg8 or soluble Atg8 on GEF activity. Analysis was carried out as in (A) with reduced Mon-Ccz1 concentrations and upon addition of His-tagged Atg8 at the indicated concentrations. (E) Quantification of the rate constants of wild-type and mutant Mon1-Ccz1 complex in the presence and absence of Atg8 for Figure 5B–C. Rate constants were calculated based on the initial slope of the GEF curve (n = 3) (Kiontke et al., 2017; Langemeyer et al., 2014). Error bars, SD. (F) Model of Mon1-Ccz1 recruitment to the autophagosome and endosomes. For details see text.

https://doi.org/10.7554/eLife.31145.021

Discussion

Previous studies showed that artificial redirection of GEFs can redirect different Rabs to other membranes (Blümer et al., 2013; Gerondopoulos et al., 2012), yet the molecular determinants that target GEFs to their correct membrane are only partially known and rarely experimentally validated. Autophagosomes form de novo and finally fuses with lysosomes (Reggiori and Ungermann, 2017). Like maturing endosomes, autophagosomes need to acquire the machinery to allow their fusion with lysosomes, including the Rab7/Ypt7 GTPase. Here we have uncovered a simple molecular mechanism that specifically targets the GEF Mon1-Ccz1 onto the surface of autophagosomes. The Ccz1 subunit has at least one conserved C-terminal LIR motif, which directly binds to the LC3 homolog Atg8. Once on autophagosomes, Mon1-Ccz1 recruits and activates the Rab7-like Ypt7 from the cytosol, which in turn can bind the HOPS tethering complex to trigger SNARE-mediated fusion. We indeed found recent evidence that Mon1-Ccz1 is sufficient to activate Ypt7, which was provided in a soluble complex with GDI, and thus triggered fusion in a reconstituted assay (Langemeyer et al., 2018). Similarly, the TRAPP GEF complexes could activate their corresponding Rab-GDI complexes on membranes (Thomas and Fromme, 2016). In agreement with this interpretation, only wild type but not LIR-mutated Mon1-Ccz1 strongly promotes Ypt7 activation in the presence of membrane-localized Atg8 (Figure 5E).

Our data imply that lipidated Atg8 is a specific determinant to redirect Mon1-Ccz1 to autophagosomes. In addition to Atg8, PI-3-P may support re-localization to both endosomes and autophagosomes (Hegedűs et al., 2016; Cabrera et al., 2014). Indeed, deletion of Atg14 in Drosophila fat cells appears to affect autophagosome fusion in addition to altering the biogenesis of these vesicles (Hegedűs et al., 2016). The generation of autophagosomal PI-3-P is required for multiple events, including efficient Atg8 lipidation (Shibutani and Yoshimori, 2014). Interestingly, Mon1-Ccz1 localization to Atg8 positive dots was not impaired if synthesis of the autophagosome-specific PI-3-P pool was blocked by atg14 deletion (Figure 2C). We consider it therefore unlikely that PI-3-P synthesis is a primary factor for Mon1-Ccz1 localization to autophagosomes. In contrast, our analysis suggests that PI-3-P may be critical for Mon1-Ccz1 activity, which could explain the defect in Ypt7 localization to autophagosomes of the atg14Δ mutant. Alternatively, PI-3-P might directly support the recruitment of Ypt7, even though we have evidence that Mon1-Ccz1 activity is most critical in this process (Langemeyer et al., 2018). How the reported PI-3-P binding (Lawrence et al., 2014; Cabrera et al., 2014) affects Mon1-Ccz1 function needs to be further dissected. Future studies will also need to explore how Mon1-Ccz1 is timely and spatially recruited to autophagosomes.

Importantly, our study reveals that Mon1-Ccz1 is functional in the endocytic pathway, when its LIR motifs are singularly mutated. This provides further evidence that Mon1-Ccz1 has a dual role and two different targeting mechanisms for two distinct organelles. By identifying the LIR mutants, we established one of the few conditions that might accumulate fully assembled autophagosomes, which are incompetent of fusing with vacuoles, while maintaining endosome-vacuole fusion and thus vacuoles functional.

In mammalian cells, additional proteins such as PLEKHM1 (McEwan et al., 2015) have been identified as factors involved in the fusion between autophagosomes and lysosomes. Interestingly, PLEKHM1 directly binds LC3-like proteins and Rab7, and could thus support HOPS-mediated tethering and fusion of autophagosomes with lysosomes. We believe that GEFs such as Mon1-Ccz1 are the most critical factors to confine Rab localization and thus determine organelle identity. The cooperation with LC3-like proteins could then provide a combinatorial code to target GEFs and additional fusion factors to autophagosomes. Interestingly, Atg8 is not homogenously distributed over the surface of forming autophagosomes (Graef et al., 2013), and could potentially cluster fusion factors to facilitate their cooperation during fusion. How Atg8 recycling and fusion are then coordinated (Abreu et al., 2017), it is yet another exciting riddle to be dissected. At least Mon1-Ccz1 localization to autophagosomes might be dispensable, once Rab7/Ypt7 is recruited and bound to HOPS.

Recent work of us and others revealed that GEFs can recruit Rab GTPases from the GDI complex to membranes (Langemeyer et al., 2018)(Thomas and Fromme, 2016). The identification of Atg8 as a determinant for Mon1-Ccz1 localization to autophagosomes provides the first example of how a GEF can be diverted to a different location. Differential spatiotemporal recruitment of GEFs allows cells to operate distinct pathways, such as autophagy and endosomal maturation, depending on their metabolic needs while employing the same machinery. For endosomal localization, Rab5-GTP has been suggested as a Mon1-Ccz1 interactor based on yeast-two-hybrid interactions (Li et al., 2015; Cui et al., 2014; Singh et al., 2014; Kinchen and Ravichandran, 2010). Future studies will need to dissect if this order of events can be indeed recapitulated in vitro and how further endosomal and autophagosomal factors specify GEF localization.

Materials and methods

Yeast strains and molecular biology

Strains and plasmids used in this study are listed in Supplementary file 1 and 2, respectively. Deletions and tagging of genes were done by homologous recombination of respective PCR fragments (Janke et al., 2004; Puig et al., 1998). Mon1 and Ccz1 mutants were generated by QuikChange mutagenesis (Stratagene, La Jolla, CA). Mon1 and Ccz1 truncation mutants have been published (Kiontke et al., 2017). Plasmids encoding GST-Atg8 and Atg8-His6 were kindly provided by Ivan Dikic (Goethe University School of Medicine, Frankfurt am Main, Germany), and Sascha Martens (University of Vienna, Austria), respectively.

Tandem affinity purification

Tandem affinity purification was performed as described (Bröcker et al., 2012; Lürick et al., 2017). Six liters of culture in YPG were grown at 30°C to OD600 of 6, and cells were harvested and lysed in lysis buffer (300 mM NaCl, 50 mM HEPES-NaOH, pH 7.4, 1.5 mM MgCl2, 1 × FY protease inhibitor mix (Serva, Germany), 0.5 mM PMSF and 1 mM DTT). Lysates were centrifuged for 1 hr at 100,000 g, and the cleared supernatant was incubated with IgG Sepharose beads (GE Healthcare, Penzberg, Germany) for 2 hr at 4°C. Beads were collected by centrifugation at 800 g for 2 min, and washed with ice cold 15 ml lysis buffer containing 0.5 mM DTT and 10% glycerol. Bound proteins were eluted by TEV cleavage overnight at 4°C. Purified proteins were analyzed on SDS-PAGE.

E.coli protein expression and purification

Atg8 was purified from E. coli BL21 (DE3) Rosetta cells. Cells were grown to an OD600 of 0.6 and induced with 0.5 mM IPTG overnight at 16°C. Cells were lysed in lysis buffer (50 mM HEPES/NaOH, pH 7.5, 150 mM NaCl, 1 mM PMSF, 1x protease inhibitor cocktail (1x = 0.1 mg/ml of leupeptin, 1 mM o-phenanthroline, 0.5 mg/ml of pepstatin A, 0.1 mM Pefabloc)). Lysates were centrifuged for 20 min at 30,000 g, and the cleared supernatant was incubated with Glutathione Sepharose (GSH) beads (for GST-tagged proteins) or Ni-NTA beads (for His-tagged proteins) for 1 hr at 4°C on a nutator. Beads were washed with 20 ml cold lysis buffer (GSH-beads) or lysis buffer containing 20 mM imidazole (Ni-NTA beads). Bound proteins were eluted with buffer containing 15 mM reduced glutathione (GSH-beads) or buffer containing 300 mM imidazole (Ni-NTA beads). Buffer was exchanged to 50 mM HEPES/NaOH, pH 7.4, 150 mM NaCl, and 10% glycerol by using a NAP-10 column (GE Healthcare, Penzberg, Germany).

GST pull down binding assays

To perform GST pull down binding assays, GST or GST-fused Atg8 wild type or Atg8 mutants or ubiquitin were used as bait, and Mon1-Ccz1 was used as a prey. GST or GST-tagged proteins (150 µg) were simultaneously incubated with GSH-beads for 1 hr at 4°C on a rotating wheel. Beads were washed three times with buffer (150 mM NaCl, 50 mM HEPES/NaOH, pH 7.4, 1.5 mM MgCl2, 0.1% NP-40), and the GSH-bound proteins were then incubated with Mon1-Ccz1 (25 µg) for 2 hr at 4°C on a rotating wheel. Beads were again washed three times in buffer. Bound proteins were eluted by boiling in SDS-sample buffer, resolved on SDS gels, and either analyzed by Coomassie Blue staining or immunoblotting with anti-CbP antibodies (Lürick et al., 2017).

Light microscopy and image analysis

Yeast cells were first cultured in YPD media to log phase, and then switched to synthetic minimal medium lacking nitrogen (SD-N) for the indicated times to induce starvation. For CMAC staining of vacuoles, cells were incubated with 0.1 CMAC for 15 min at 30°C and subsequent washed with medium. Cells were imaged on a Deltavision Elite imaging system based on an inverted microscopy, equipped with 100x NA 1.49 and 60x NA 1.40 objectives, a sCMOS camera (PCO, Kelheim, Germany), an InsightSSI illumination system, and SoftWoRx software (Applied Precision, Issaquah, WA). Stacks of 6 or 8 images with 0.2 µm spacing were taken for constrained-iterative deconvolution (SoftWoRx) and quantification.

GEF assay on multilamellar vesicles (MLVs)

GEF assays were performed as described (Nordmann et al., 2010; Cabrera et al., 2014). 60 pmoles Atg8-His were incubated with 60 µl multilamellar vesicles (MLVs, 15 mM) of the following composition (palmitoyloleoyl phosphatidylcholine, 84 mol%, palmitoyloleoyl phosphatidylcholine 10 mol%, DOGS-NTA (1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid)succinyl]), 6 mol%) for 15 min at 25°C. 500 pmoles Ypt7-His were preloaded with MANT-GDP, and incubated with MLVs for 5 min at 25°C before addition of the Mon1–Ccz1 complex. MANT fluorescence was detected in a SpectraMax M3 Multi-Mode Microplate Reader (Molecular Devices, Germany). Samples were excited at 355 nm and fluorescence was detected at 448 nm. After 20–30 min, 0.1 mM GTP was added to trigger the exchange reaction. The decrease of MANT-GDP fluorescence is an indicator of nucleotide exchange.

Giant Ape1 assay

Yeast cells (carry the plasmid pRS315-CUP1pr-BFP-APE1) were grown overnight in SDC-LEU medium, then diluted to early log phase next morning. 250 µM CuSO4 was added to induce the giant Ape1 oligomer formation for 4 hr, and cultures were then switched to SD-N medium containing 250 µM CuSO4 for 1 hr to induce autophagy.

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    643. M Fukuda
    644. S Fulda
    645. C Fusco
    646. B Gabryel
    647. M Gaestel
    648. P Gailly
    649. M Gajewska
    650. S Galadari
    651. G Galili
    652. I Galindo
    653. MF Galindo
    654. G Galliciotti
    655. L Galluzzi
    656. L Galluzzi
    657. V Galy
    658. N Gammoh
    659. S Gandy
    660. AK Ganesan
    661. S Ganesan
    662. IG Ganley
    663. M Gannagé
    664. FB Gao
    665. F Gao
    666. JX Gao
    667. L García Nannig
    668. E García Véscovi
    669. M Garcia-Macía
    670. C Garcia-Ruiz
    671. AD Garg
    672. PK Garg
    673. R Gargini
    674. NC Gassen
    675. D Gatica
    676. E Gatti
    677. J Gavard
    678. E Gavathiotis
    679. L Ge
    680. P Ge
    681. S Ge
    682. PW Gean
    683. V Gelmetti
    684. AA Genazzani
    685. J Geng
    686. P Genschik
    687. L Gerner
    688. JE Gestwicki
    689. DA Gewirtz
    690. S Ghavami
    691. E Ghigo
    692. D Ghosh
    693. AM Giammarioli
    694. F Giampieri
    695. C Giampietri
    696. A Giatromanolaki
    697. DJ Gibbings
    698. L Gibellini
    699. SB Gibson
    700. V Ginet
    701. A Giordano
    702. F Giorgini
    703. E Giovannetti
    704. SE Girardin
    705. S Gispert
    706. S Giuliano
    707. CL Gladson
    708. A Glavic
    709. M Gleave
    710. N Godefroy
    711. RM Gogal
    712. K Gokulan
    713. GH Goldman
    714. D Goletti
    715. MS Goligorsky
    716. AV Gomes
    717. LC Gomes
    718. H Gomez
    719. C Gomez-Manzano
    720. R Gómez-Sánchez
    721. DA Gonçalves
    722. E Goncu
    723. Q Gong
    724. C Gongora
    725. CB Gonzalez
    726. P Gonzalez-Alegre
    727. P Gonzalez-Cabo
    728. RA González-Polo
    729. IS Goping
    730. C Gorbea
    731. NV Gorbunov
    732. DR Goring
    733. AM Gorman
    734. SM Gorski
    735. S Goruppi
    736. S Goto-Yamada
    737. C Gotor
    738. RA Gottlieb
    739. I Gozes
    740. D Gozuacik
    741. Y Graba
    742. M Graef
    743. GE Granato
    744. GD Grant
    745. S Grant
    746. GL Gravina
    747. DR Green
    748. A Greenhough
    749. MT Greenwood
    750. B Grimaldi
    751. F Gros
    752. C Grose
    753. JF Groulx
    754. F Gruber
    755. P Grumati
    756. T Grune
    757. JL Guan
    758. KL Guan
    759. B Guerra
    760. C Guillen
    761. K Gulshan
    762. J Gunst
    763. C Guo
    764. L Guo
    765. M Guo
    766. W Guo
    767. XG Guo
    768. AA Gust
    769. ÅB Gustafsson
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    771. MG Gutierrez
    772. HS Gwak
    773. A Haas
    774. JE Haber
    775. S Hadano
    776. M Hagedorn
    777. DR Hahn
    778. AJ Halayko
    779. A Hamacher-Brady
    780. K Hamada
    781. A Hamai
    782. A Hamann
    783. M Hamasaki
    784. I Hamer
    785. Q Hamid
    786. EM Hammond
    787. F Han
    788. W Han
    789. JT Handa
    790. JA Hanover
    791. M Hansen
    792. M Harada
    793. L Harhaji-Trajkovic
    794. JW Harper
    795. AH Harrath
    796. AL Harris
    797. J Harris
    798. U Hasler
    799. P Hasselblatt
    800. K Hasui
    801. RG Hawley
    802. TS Hawley
    803. C He
    804. CY He
    805. F He
    806. G He
    807. RR He
    808. XH He
    809. YW He
    810. YY He
    811. JK Heath
    812. MJ Hébert
    813. RA Heinzen
    814. GV Helgason
    815. M Hensel
    816. EP Henske
    817. C Her
    818. PK Herman
    819. A Hernández
    820. C Hernandez
    821. S Hernández-Tiedra
    822. C Hetz
    823. PR Hiesinger
    824. K Higaki
    825. S Hilfiker
    826. BG Hill
    827. JA Hill
    828. WD Hill
    829. K Hino
    830. D Hofius
    831. P Hofman
    832. GU Höglinger
    833. J Höhfeld
    834. MK Holz
    835. Y Hong
    836. DA Hood
    837. JJ Hoozemans
    838. T Hoppe
    839. C Hsu
    840. CY Hsu
    841. LC Hsu
    842. D Hu
    843. G Hu
    844. HM Hu
    845. H Hu
    846. MC Hu
    847. YC Hu
    848. ZW Hu
    849. F Hua
    850. Y Hua
    851. C Huang
    852. HL Huang
    853. KH Huang
    854. KY Huang
    855. S Huang
    856. S Huang
    857. WP Huang
    858. YR Huang
    859. Y Huang
    860. Y Huang
    861. TB Huber
    862. P Huebbe
    863. WK Huh
    864. JJ Hulmi
    865. GM Hur
    866. JH Hurley
    867. Z Husak
    868. SN Hussain
    869. S Hussain
    870. JJ Hwang
    871. S Hwang
    872. TI Hwang
    873. A Ichihara
    874. Y Imai
    875. C Imbriano
    876. M Inomata
    877. T Into
    878. V Iovane
    879. JL Iovanna
    880. RV Iozzo
    881. NY Ip
    882. JE Irazoqui
    883. P Iribarren
    884. Y Isaka
    885. AJ Isakovic
    886. H Ischiropoulos
    887. JS Isenberg
    888. M Ishaq
    889. H Ishida
    890. I Ishii
    891. JE Ishmael
    892. C Isidoro
    893. K Isobe
    894. E Isono
    895. S Issazadeh-Navikas
    896. K Itahana
    897. E Itakura
    898. AI Ivanov
    899. AK Iyer
    900. JM Izquierdo
    901. Y Izumi
    902. V Izzo
    903. M Jäättelä
    904. N Jaber
    905. DJ Jackson
    906. WT Jackson
    907. TG Jacob
    908. TS Jacques
    909. C Jagannath
    910. A Jain
    911. NR Jana
    912. BK Jang
    913. A Jani
    914. B Janji
    915. PR Jannig
    916. PJ Jansson
    917. S Jean
    918. M Jendrach
    919. JH Jeon
    920. N Jessen
    921. EB Jeung
    922. K Jia
    923. L Jia
    924. H Jiang
    925. H Jiang
    926. L Jiang
    927. T Jiang
    928. X Jiang
    929. X Jiang
    930. X Jiang
    931. Y Jiang
    932. Y Jiang
    933. A Jiménez
    934. C Jin
    935. H Jin
    936. L Jin
    937. M Jin
    938. S Jin
    939. UK Jinwal
    940. EK Jo
    941. T Johansen
    942. DE Johnson
    943. GV Johnson
    944. JD Johnson
    945. E Jonasch
    946. C Jones
    947. LA Joosten
    948. J Jordan
    949. AM Joseph
    950. B Joseph
    951. AM Joubert
    952. D Ju
    953. J Ju
    954. HF Juan
    955. K Juenemann
    956. G Juhász
    957. HS Jung
    958. JU Jung
    959. YK Jung
    960. H Jungbluth
    961. MJ Justice
    962. B Jutten
    963. NO Kaakoush
    964. K Kaarniranta
    965. A Kaasik
    966. T Kabuta
    967. B Kaeffer
    968. K Kågedal
    969. A Kahana
    970. S Kajimura
    971. O Kakhlon
    972. M Kalia
    973. DV Kalvakolanu
    974. Y Kamada
    975. K Kambas
    976. VO Kaminskyy
    977. HH Kampinga
    978. M Kandouz
    979. C Kang
    980. R Kang
    981. TC Kang
    982. T Kanki
    983. TD Kanneganti
    984. H Kanno
    985. AG Kanthasamy
    986. M Kantorow
    987. M Kaparakis-Liaskos
    988. O Kapuy
    989. V Karantza
    990. MR Karim
    991. P Karmakar
    992. A Kaser
    993. S Kaushik
    994. T Kawula
    995. AM Kaynar
    996. PY Ke
    997. ZJ Ke
    998. JH Kehrl
    999. KE Keller
    1000. JK Kemper
    1001. AK Kenworthy
    1002. O Kepp
    1003. A Kern
    1004. S Kesari
    1005. D Kessel
    1006. R Ketteler
    1007. IC Kettelhut
    1008. B Khambu
    1009. MM Khan
    1010. VK Khandelwal
    1011. S Khare
    1012. JG Kiang
    1013. AA Kiger
    1014. A Kihara
    1015. AL Kim
    1016. CH Kim
    1017. DR Kim
    1018. DH Kim
    1019. EK Kim
    1020. HY Kim
    1021. HR Kim
    1022. JS Kim
    1023. JH Kim
    1024. JC Kim
    1025. JH Kim
    1026. KW Kim
    1027. MD Kim
    1028. MM Kim
    1029. PK Kim
    1030. SW Kim
    1031. SY Kim
    1032. YS Kim
    1033. Y Kim
    1034. A Kimchi
    1035. AC Kimmelman
    1036. T Kimura
    1037. JS King
    1038. K Kirkegaard
    1039. V Kirkin
    1040. LA Kirshenbaum
    1041. S Kishi
    1042. Y Kitajima
    1043. K Kitamoto
    1044. Y Kitaoka
    1045. K Kitazato
    1046. RA Kley
    1047. WT Klimecki
    1048. M Klinkenberg
    1049. J Klucken
    1050. H Knævelsrud
    1051. E Knecht
    1052. L Knuppertz
    1053. JL Ko
    1054. S Kobayashi
    1055. JC Koch
    1056. C Koechlin-Ramonatxo
    1057. U Koenig
    1058. YH Koh
    1059. K Köhler
    1060. SD Kohlwein
    1061. M Koike
    1062. M Komatsu
    1063. E Kominami
    1064. D Kong
    1065. HJ Kong
    1066. EG Konstantakou
    1067. BT Kopp
    1068. T Korcsmaros
    1069. L Korhonen
    1070. VI Korolchuk
    1071. NV Koshkina
    1072. Y Kou
    1073. MI Koukourakis
    1074. C Koumenis
    1075. AL Kovács
    1076. T Kovács
    1077. WJ Kovacs
    1078. D Koya
    1079. C Kraft
    1080. D Krainc
    1081. H Kramer
    1082. T Kravic-Stevovic
    1083. W Krek
    1084. C Kretz-Remy
    1085. R Krick
    1086. M Krishnamurthy
    1087. J Kriston-Vizi
    1088. G Kroemer
    1089. MC Kruer
    1090. R Kruger
    1091. NT Ktistakis
    1092. K Kuchitsu
    1093. C Kuhn
    1094. AP Kumar
    1095. A Kumar
    1096. A Kumar
    1097. D Kumar
    1098. D Kumar
    1099. R Kumar
    1100. S Kumar
    1101. M Kundu
    1102. HJ Kung
    1103. A Kuno
    1104. SH Kuo
    1105. J Kuret
    1106. T Kurz
    1107. T Kwok
    1108. TK Kwon
    1109. YT Kwon
    1110. I Kyrmizi
    1111. AR La Spada
    1112. F Lafont
    1113. T Lahm
    1114. A Lakkaraju
    1115. T Lam
    1116. T Lamark
    1117. S Lancel
    1118. TH Landowski
    1119. DJ Lane
    1120. JD Lane
    1121. C Lanzi
    1122. P Lapaquette
    1123. LR Lapierre
    1124. J Laporte
    1125. J Laukkarinen
    1126. GW Laurie
    1127. S Lavandero
    1128. L Lavie
    1129. MJ LaVoie
    1130. BY Law
    1131. HK Law
    1132. KB Law
    1133. R Layfield
    1134. PA Lazo
    1135. L Le Cam
    1136. KG Le Roch
    1137. H Le Stunff
    1138. V Leardkamolkarn
    1139. M Lecuit
    1140. BH Lee
    1141. CH Lee
    1142. EF Lee
    1143. GM Lee
    1144. HJ Lee
    1145. H Lee
    1146. JK Lee
    1147. J Lee
    1148. JH Lee
    1149. JH Lee
    1150. M Lee
    1151. MS Lee
    1152. PJ Lee
    1153. SW Lee
    1154. SJ Lee
    1155. SJ Lee
    1156. SY Lee
    1157. SH Lee
    1158. SS Lee
    1159. SJ Lee
    1160. S Lee
    1161. YR Lee
    1162. YJ Lee
    1163. YH Lee
    1164. C Leeuwenburgh
    1165. S Lefort
    1166. R Legouis
    1167. J Lei
    1168. QY Lei
    1169. DA Leib
    1170. G Leibowitz
    1171. I Lekli
    1172. SD Lemaire
    1173. JJ Lemasters
    1174. MK Lemberg
    1175. A Lemoine
    1176. S Leng
    1177. G Lenz
    1178. P Lenzi
    1179. LO Lerman
    1180. D Lettieri Barbato
    1181. JI Leu
    1182. HY Leung
    1183. B Levine
    1184. PA Lewis
    1185. F Lezoualc'h
    1186. C Li
    1187. F Li
    1188. FJ Li
    1189. J Li
    1190. K Li
    1191. L Li
    1192. M Li
    1193. M Li
    1194. Q Li
    1195. R Li
    1196. S Li
    1197. W Li
    1198. W Li
    1199. X Li
    1200. Y Li
    1201. J Lian
    1202. C Liang
    1203. Q Liang
    1204. Y Liao
    1205. J Liberal
    1206. PP Liberski
    1207. P Lie
    1208. AP Lieberman
    1209. HJ Lim
    1210. KL Lim
    1211. K Lim
    1212. RT Lima
    1213. CS Lin
    1214. CF Lin
    1215. F Lin
    1216. F Lin
    1217. FC Lin
    1218. K Lin
    1219. KH Lin
    1220. PH Lin
    1221. T Lin
    1222. WW Lin
    1223. YS Lin
    1224. Y Lin
    1225. R Linden
    1226. D Lindholm
    1227. LM Lindqvist
    1228. P Lingor
    1229. A Linkermann
    1230. LA Liotta
    1231. MM Lipinski
    1232. VA Lira
    1233. MP Lisanti
    1234. PB Liton
    1235. B Liu
    1236. C Liu
    1237. CF Liu
    1238. F Liu
    1239. HJ Liu
    1240. J Liu
    1241. JJ Liu
    1242. JL Liu
    1243. K Liu
    1244. L Liu
    1245. L Liu
    1246. Q Liu
    1247. RY Liu
    1248. S Liu
    1249. S Liu
    1250. W Liu
    1251. XD Liu
    1252. X Liu
    1253. XH Liu
    1254. X Liu
    1255. X Liu
    1256. X Liu
    1257. Y Liu
    1258. Y Liu
    1259. Z Liu
    1260. Z Liu
    1261. JP Liuzzi
    1262. G Lizard
    1263. M Ljujic
    1264. IJ Lodhi
    1265. SE Logue
    1266. BL Lokeshwar
    1267. YC Long
    1268. S Lonial
    1269. B Loos
    1270. C López-Otín
    1271. C López-Vicario
    1272. M Lorente
    1273. PL Lorenzi
    1274. P Lõrincz
    1275. M Los
    1276. MT Lotze
    1277. PE Lovat
    1278. B Lu
    1279. B Lu
    1280. J Lu
    1281. Q Lu
    1282. SM Lu
    1283. S Lu
    1284. Y Lu
    1285. F Luciano
    1286. S Luckhart
    1287. JM Lucocq
    1288. P Ludovico
    1289. A Lugea
    1290. NW Lukacs
    1291. JJ Lum
    1292. AH Lund
    1293. H Luo
    1294. J Luo
    1295. S Luo
    1296. C Luparello
    1297. T Lyons
    1298. J Ma
    1299. Y Ma
    1300. Y Ma
    1301. Z Ma
    1302. J Machado
    1303. GM Machado-Santelli
    1304. F Macian
    1305. GC MacIntosh
    1306. JP MacKeigan
    1307. KF Macleod
    1308. JD MacMicking
    1309. LA MacMillan-Crow
    1310. F Madeo
    1311. M Madesh
    1312. J Madrigal-Matute
    1313. A Maeda
    1314. T Maeda
    1315. G Maegawa
    1316. E Maellaro
    1317. H Maes
    1318. M Magariños
    1319. K Maiese
    1320. TK Maiti
    1321. L Maiuri
    1322. MC Maiuri
    1323. CG Maki
    1324. R Malli
    1325. W Malorni
    1326. A Maloyan
    1327. F Mami-Chouaib
    1328. N Man
    1329. JD Mancias
    1330. EM Mandelkow
    1331. MA Mandell
    1332. AA Manfredi
    1333. SN Manié
    1334. C Manzoni
    1335. K Mao
    1336. Z Mao
    1337. ZW Mao
    1338. P Marambaud
    1339. AM Marconi
    1340. Z Marelja
    1341. G Marfe
    1342. M Margeta
    1343. E Margittai
    1344. M Mari
    1345. FV Mariani
    1346. C Marin
    1347. S Marinelli
    1348. G Mariño
    1349. I Markovic
    1350. R Marquez
    1351. AM Martelli
    1352. S Martens
    1353. KR Martin
    1354. SJ Martin
    1355. S Martin
    1356. MA Martin-Acebes
    1357. P Martín-Sanz
    1358. C Martinand-Mari
    1359. W Martinet
    1360. J Martinez
    1361. N Martinez-Lopez
    1362. U Martinez-Outschoorn
    1363. M Martínez-Velázquez
    1364. M Martinez-Vicente
    1365. WK Martins
    1366. H Mashima
    1367. JA Mastrianni
    1368. G Matarese
    1369. P Matarrese
    1370. R Mateo
    1371. S Matoba
    1372. N Matsumoto
    1373. T Matsushita
    1374. A Matsuura
    1375. T Matsuzawa
    1376. MP Mattson
    1377. S Matus
    1378. N Maugeri
    1379. C Mauvezin
    1380. A Mayer
    1381. D Maysinger
    1382. GD Mazzolini
    1383. MK McBrayer
    1384. K McCall
    1385. C McCormick
    1386. GM McInerney
    1387. SC McIver
    1388. S McKenna
    1389. JJ McMahon
    1390. IA McNeish
    1391. F Mechta-Grigoriou
    1392. JP Medema
    1393. DL Medina
    1394. K Megyeri
    1395. M Mehrpour
    1396. JL Mehta
    1397. Y Mei
    1398. UC Meier
    1399. AJ Meijer
    1400. A Meléndez
    1401. G Melino
    1402. S Melino
    1403. EJ de Melo
    1404. MA Mena
    1405. MD Meneghini
    1406. JA Menendez
    1407. R Menezes
    1408. L Meng
    1409. LH Meng
    1410. S Meng
    1411. R Menghini
    1412. AS Menko
    1413. RF Menna-Barreto
    1414. MB Menon
    1415. MA Meraz-Ríos
    1416. G Merla
    1417. L Merlini
    1418. AM Merlot
    1419. A Meryk
    1420. S Meschini
    1421. JN Meyer
    1422. MT Mi
    1423. CY Miao
    1424. L Micale
    1425. S Michaeli
    1426. C Michiels
    1427. AR Migliaccio
    1428. AS Mihailidou
    1429. D Mijaljica
    1430. K Mikoshiba
    1431. E Milan
    1432. L Miller-Fleming
    1433. GB Mills
    1434. IG Mills
    1435. G Minakaki
    1436. BA Minassian
    1437. XF Ming
    1438. F Minibayeva
    1439. EA Minina
    1440. JD Mintern
    1441. S Minucci
    1442. A Miranda-Vizuete
    1443. CH Mitchell
    1444. S Miyamoto
    1445. K Miyazawa
    1446. N Mizushima
    1447. K Mnich
    1448. B Mograbi
    1449. S Mohseni
    1450. LF Moita
    1451. M Molinari
    1452. M Molinari
    1453. AB Møller
    1454. B Mollereau
    1455. F Mollinedo
    1456. M Mongillo
    1457. MM Monick
    1458. S Montagnaro
    1459. C Montell
    1460. DJ Moore
    1461. MN Moore
    1462. R Mora-Rodriguez
    1463. PI Moreira
    1464. E Morel
    1465. MB Morelli
    1466. S Moreno
    1467. MJ Morgan
    1468. A Moris
    1469. Y Moriyasu
    1470. JL Morrison
    1471. LA Morrison
    1472. E Morselli
    1473. J Moscat
    1474. PL Moseley
    1475. S Mostowy
    1476. E Motori
    1477. D Mottet
    1478. JC Mottram
    1479. CE Moussa
    1480. VE Mpakou
    1481. H Mukhtar
    1482. JM Mulcahy Levy
    1483. S Muller
    1484. R Muñoz-Moreno
    1485. C Muñoz-Pinedo
    1486. C Münz
    1487. ME Murphy
    1488. JT Murray
    1489. A Murthy
    1490. IU Mysorekar
    1491. IR Nabi
    1492. M Nabissi
    1493. GA Nader
    1494. Y Nagahara
    1495. Y Nagai
    1496. K Nagata
    1497. A Nagelkerke
    1498. P Nagy
    1499. SR Naidu
    1500. S Nair
    1501. H Nakano
    1502. H Nakatogawa
    1503. M Nanjundan
    1504. G Napolitano
    1505. NI Naqvi
    1506. R Nardacci
    1507. DP Narendra
    1508. M Narita
    1509. AC Nascimbeni
    1510. R Natarajan
    1511. LC Navegantes
    1512. ST Nawrocki
    1513. TY Nazarko
    1514. VY Nazarko
    1515. T Neill
    1516. LM Neri
    1517. MG Netea
    1518. RT Netea-Maier
    1519. BM Neves
    1520. PA Ney
    1521. IP Nezis
    1522. HT Nguyen
    1523. HP Nguyen
    1524. AS Nicot
    1525. H Nilsen
    1526. P Nilsson
    1527. M Nishimura
    1528. I Nishino
    1529. M Niso-Santano
    1530. H Niu
    1531. RA Nixon
    1532. VC Njar
    1533. T Noda
    1534. AA Noegel
    1535. EM Nolte
    1536. E Norberg
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