The abundant, highly conserved AAA+-type ATPase p97 (also known as VCP in mammals and Cdc48 in plants and lower eukaryotes) plays a central role in the maintenance of protein and organelle homeostasis as well as genome integrity (reviewed in Ahlstedt et al., 2022; Franz et al., 2016a; Papadopoulos and Meyer, 2017). The best-characterized function of p97 is the segregation of ubiquitin-modified proteins in various protein quality control pathways for their subsequent degradation by the 26S proteasome (Brandman et al., 2012; Dantuma and Hoppe, 2012; Tanaka et al., 2010; Ye et al., 2001). p97 is also involved in the lysosomal degradation of endocytic cargo (Ritz et al., 2011) and in the selective autophagy of protein aggregates, stress granules, as well as damaged mitochondria and lysosomes (Buchan et al., 2013; Ju et al., 2008; Kim et al., 2013; Papadopoulos et al., 2017; Tanaka et al., 2010; Turakhiya et al., 2018). Moreover, p97 possesses a number of crucial nuclear functions, for instance, in DNA replication and DNA damage repair (Acs et al., 2011; Davis et al., 2012; Franz et al., 2011; Maric et al., 2014; Meerang et al., 2011; Moreno et al., 2014; Mosbech et al., 2012; Mouysset et al., 2008; Raman et al., 2011). Importantly, mutational perturbation of p97 function causes the neuromuscular degenerative disease multisystem proteinopathy 1 (MSP1) (Johnson et al., 2010; Pfeffer et al., 2022; Watts et al., 2004), and several cancers as well as viral and bacterial pathogens rely on p97 activity, making p97 an attractive target for therapeutic intervention (Das and Dudley, 2021; Deshaies, 2014; Humphreys et al., 2009; Huryn et al., 2020).

The molecular basis underlying the diverse cellular functions of p97 is the partial or complete unfolding of substrate proteins by threading through the ring-shaped p97 homohexamer in an ATP hydrolysis-driven process (Blythe et al., 2017; Bodnar and Rapoport, 2017; Buchberger, 2022). Since p97 itself lacks appreciable specificity for its physiological substrates, a large number of cofactor proteins control substrate binding, subcellular localization, and oligomeric state of p97 (reviewed in Buchberger et al., 2015). Some of these cofactors bind to p97 in a mutually exclusive manner and define functionally distinct, major p97 complexes: a heterodimer of UFD1 (also known as UFD1L) and NPL4 (also known as NPLOC4) recruits ubiquitylated substrates for p97-dependent unfolding and subsequent proteasomal degradation or processing (Bays et al., 2001; Jarosch et al., 2002; Rape et al., 2001; Ye et al., 2001), whereas UBXN6 (also known as UBXD1) controls p97 functions in lysosomal and autophagic degradation pathways (Papadopoulos et al., 2017; Ritz et al., 2011) and SEP domain-containing cofactors such as p47 (also known as NSFL1C) and UBXN2B (also known as p37) mediate the maturation of protein phosphatase 1 complexes (Weith et al., 2018). At least in the case of p97-UFD1-NPL4, auxiliary cofactors from the UBA-UBX family can fine-tune the subcellular localization and/or substrate specificity of a major p97 complex (Buchberger et al., 2015; Schuberth and Buchberger, 2008). For example, the yeast cofactor Ubx2 recruits Cdc48-Ufd1-Npl4 to the endoplasmic reticulum (ER) and mitochondria to promote ER- and outer mitochondrial membrane-associated protein degradation, respectively (Mårtensson et al., 2019; Neuber et al., 2005; Schuberth and Buchberger, 2005). Similarly, the metazoan cofactors UBXN7 and FAF1 direct p97-UFD1-NPL4 to nuclear chromatin to promote the removal of ubiquitylated substrates such as CDT1 and the CMG helicase (Franz et al., 2016b; Fujisawa et al., 2022; Kochenova et al., 2022; Tarcan et al., 2022).

The majority of cofactors interact with p97 through a small number of defined domains/motifs, including the UBX(-like) domain, the PUB and PUL domains, the SHP box, the VCP interacting motif (VIM), and the VCP binding motif (VBM) (reviewed in Buchberger et al., 2015). However, some p97 interactors do not possess any of these canonical binding motifs, suggesting that the current inventory of p97 cofactors is incomplete and, hence, that the full scope of the p97–cofactor network is far from being understood. Examples illustrating this point include ZFAND1 (yeast Cuz1) and GIGYF1/2 (yeast Smy2), which were recently shown to regulate p97 functions in stress granule clearance (Turakhiya et al., 2018) and the transcription stress response (Lehner et al., 2022), respectively.

Here, we report the identification of the previously uncharacterized, evolutionarily conserved FAM104 protein family as p97 cofactors. We show that the human FAM104 family members VCF1 and VCF2 bind p97 directly via a non-canonical helical motif and that they associate with different p97 complexes in cells. We demonstrate that VCF1/2 promote the nuclear localization of p97 and that their loss causes impaired growth and hypersensitivity to chemical inhibition of p97.

In this study, we characterized FAM104 proteins as a family of evolutionarily conserved p97 interactors and identified their C-terminal helix as a novel p97 binding motif. We showed that the human FAM104 proteins VCF1 and VCF2 associate with p97 complexes containing the cofactors UFD-NPL4, FAF1, UBXN7, and UBXN2B in living cells, and that they efficiently recruit p97 to the nucleus. Loss of VCF1/2 reduced nuclear p97 levels, impaired cell growth, and caused hypersensitivity to p97 inhibition in the absence and presence of DNA damage, indicating that VCF1/2 support optimal p97 activity in the nuclear compartment.

Whereas VCF2 had not been reported to interact with p97 before, VCF1 (FAM104A) was identified as a p97 interactor in several high-throughput proteomic and yeast two-hybrid screening projects (Fogeron et al., 2013; Haenig et al., 2020; Hein et al., 2015; Huttlin et al., 2017; Luck et al., 2020; Rolland et al., 2014). However, the interaction between p97 and VCF1 was not further validated in any of these previous studies. In fact, the validation of p97 binding is complicated by the existence of five different isoforms, of which only three (isoforms 1, 2, and 5) contain the p97-interacting C-terminal helix. The existence of p97 binding and non-binding isoforms of VCF1 and 2 in humans also initially obscured the prevalence of FAM104 proteins in the animal kingdom. Nevertheless, bioinformatic searches using the C-terminal p97 binding helix as query readily identified homologs in all five vertebrate classes as well as in Saccoglossus and sea urchin, leading to the subsequent identification of numerous invertebrate homologs (Figure 1—figure supplement 1A). Outside of the chordates, FAM104 proteins are found in many arthropods (insects, spiders, crustaceans) and selected other invertebrate lineages, including mollusks (octopi, snails), tardigrades, and rotifers, but are absent in nematodes, protists, plants, and fungi. The three human p97-interacting VCF1 isoforms possess an N-terminal 74-residue extension exclusively found in eutheria, a 21-residue insertion after residue 107 (numbering referring to isoform 1/2) that is found in mammals, birds, and reptiles, or both (Figure 1A and B). Amphibian, fish, and invertebrate homologs contain neither insertion and are therefore more similar to human VCF2 with respect to their overall organization. The widespread occurrence of FAM104 proteins strongly suggests a conserved function, even though very little information is available for non-human homologs. The fly homolog CG14229 lacks any functional annotations, whereas mouse Vcf1 (Fam104a) was reported to interact with ubiquitin (Zhang et al., 2017). The binding preference for K6-, K48-, and K29-linked di-ubiquitin observed in that study closely resembled that of p97, suggesting that Vcf1 did not bind ubiquitin directly, but in the context of a p97–cofactor complex such as p97-Ufd1-Npl4.

Here, we showed for the first time that FAM104 proteins and p97 interact directly via their highly conserved C-terminal alpha-helix and N domain, respectively (Figures 1 and 2). Structural modeling revealed that the C-terminal helix binds to the subdomain cleft of the p97 N domain. Interestingly, the position of the VCF1 helix in the model is similar to those of the helical VIM and VBM p97 binding motifs in the absence of any significant sequence similarity (Buchberger et al., 2015; Hänzelmann and Schindelin, 2011; Lim et al., 2016). Even the respective key p97-contacting residues are distinct, with N188 and L191 in the C-terminal helix of VCF1 versus predominantly arginine residues in VIM and VBM. The finding that alpha-helices can efficiently bind to the N subdomain cleft via just one or two key residues underlines the plasticity of this binding interface and raises the intriguing possibility that additional interactors bind p97 through yet other helical motifs.

Our cell-based experiments revealed a significant effect of VCF1/2 on the subcellular localization of p97 (4—6). Their overexpression resulted in a strong increase in p97 nuclear localization and, for VCF1 isoforms 1 and 2, chromatin association, whereas both CRISPR/Cas9-mediated deletion and siRNA-mediated depletion caused a decrease in nuclear p97 levels. While we were unable to detect endogenous VCF1/2 due to the lack of suitably sensitive antibodies, the highly consistent effects of the deletion and depletion experiments on nuclear p97 levels provide strong indirect evidence that endogenous VCF1/2 indeed localize to the nucleus, in agreement with their potent cNLS and the robust nuclear accumulation of ectopically expressed VCF1/2. Because the de(p)letion of VCF1 alone had similar effects as the VCF1/2 double knockout in these experiments, VCF1 apparently plays a more important role for the nuclear localization of p97 than VCF2, at least in HeLa and HEK293T cells.

p97 homologs from yeast to mammals possess a relatively weak potential cNLS (residues K60-R65 in human p97, score 5 according to cNLS mapper). Available three-dimensional structures of p97 suggest that this potential cNLS is part of a beta-hairpin in the N domain that is unlikely to be constitutively exposed due to nucleotide-dependent conformational changes of and cofactor binding to the N domain. Interestingly, an additional, functional bi-partite cNLS found closer to the N terminus in yeast Cdc48 (Madeo et al., 1998) is conserved in several p97 homologs from organisms lacking FAM104 proteins, but lost or poorly conserved in most p97 homologs from organisms possessing FAM104 proteins (Figure 1—figure supplement 1C). This raises the intriguing possibility that FAM104 proteins compensate the loss of the functional bipartite cNLS in the latter p97 homologs by exposing a very strong cNLS that is connected via a long, flexible region with the C-terminal helix tightly interacting with the p97 N domain. This speculation is further supported by our finding that the fusion of the strong SV40 cNLS to the N terminus of p97 can fully compensate for the loss of VCF1/2 with respect to p97 nuclear localization (Figure 6E and F).

On a more general note, our study underscores the importance of a sufficiently high number of NLSs that has to be present on large cargoes for their efficient nuclear import. In a recent quantitative study, a model cargo of roughly the same size as the p97 hexamer, MS2^S37P, had to be decorated with at least 10 NLSs for detectable nuclear import (Paci et al., 2020), suggesting that the six moderately strong and potentially masked cNLSs in the p97 hexamer are insufficient and have to be assisted by the strong cNLSs of VCF1/2. Since de(p)letion of VCF1/2 caused only a partial reduction in nuclear p97 levels in our experiments, it is likely that additional nuclear cofactors such as UBXN7 with its strong cNLS contribute to the efficient nuclear targeting of p97. Intriguingly, two other small proteins possessing strong NLSs were recently found to possess functions analogous to VCF1/2 in the nuclear import of essential protein complexes of the ubiquitin proteasome system. AKIRIN2 and HAPSTR1 promote the nuclear import of the assembled 20S proteasome (de Almeida et al., 2021) and of the E3 ligase HUWE1 (Monda et al., 2023), respectively, indicating that the decoration of protein complexes with small, NLS-containing interaction partners is a general strategy of cells.

We were able to show that VCF1 and 2 associate with the major p97-UFD1-NPL4 complex (Figure 3), potentially implicating FAM104 proteins in nuclear p97 functions such as DNA damage repair, regulation of DNA replication, and control of transcription. Consistent with this possibility, isoforms 1 and 2 of VCF1 bound the auxiliary cofactors UBXN7 and FAF1 (Figure 3) and promoted the chromatin association of p97 upon overexpression (Figure 5). The finding that VCF1/2 can also associate with the p97-UBXN2B complex involved in protein phosphatase 1 regulation (Figure 3A and Figure 3—figure supplement 1A) is intriguing as it indicates that FAM104 family proteins are likely to control p97 functions beyond proteasomal degradation pathways. While it is possible that the strong chromatin association of p97 is a consequence of overexpressing the chromatin-binding VCF1 isoforms 1 and 2 and/or of the massive loss of cofactor interactions observed under this condition (Figure 3), the impact of VCF1/2 on p97 nuclear levels was also observed in immunofluorescence microscopy upon the much weaker ectopic expression of VCF1 isoform 5 and VCF2 isoform 3 preserving p97-cofactor complexes, as well as upon de(p)letion of VCF1/2. Thus, the accumulated evidence strongly supports a direct regulatory function of VCF1/2 on the nuclear localization of p97. It is hardly compatible with the scenario that the observed relocalizations of p97 are merely secondary, compensatory effects of increased or reduced VCF1/2 levels, respectively.

While the finding that VCF1/2 double-knockout cells are hypersensitive to p97 inhibition in the absence and presence of the DNA damaging agent camptothecin (Figure 7B and C) is in line with an involvement of VCF1/2 in p97-dependent DNA damage repair processes, we were unable to detect a camptothecin sensitivity in the absence of p97 inhibitor. The partial reduction of VCF1 expression by not more than 50% in the knockout cell pools (Figure 7—figure supplement 2) is likely to prevent the detection of more severe phenotypes. It is conceivable that the decrease in nuclear p97 levels by 25% under these conditions is insufficient to severely compromise p97-dependent nuclear processes and/or that these essential processes are safeguarded by redundant p97 cofactors. Importantly, we found that chemical inhibition reduces nuclear p97 levels and further aggravates the effect of VCF1/2 deletion on the nuclear localization of p97 (Figure 7E and F), strongly suggesting that the cellular basis for the synthetic growth defect observed upon combined VCF1/2 deletion and inhibitor treatment are limiting nuclear levels and activities of p97.

The nuclear recruitment function of FAM104 proteins is reminiscent of two other small p97 interactors, SVIP and VIMP (also known as SELENOS, selenoprotein S). SVIP is myristoyl-anchored to the lysosomal membrane, whereas VIMP is a single-spanning ER membrane protein. It therefore appears that FAM104 proteins, SVIP, and VIMP recruit p97 to distinct subcellular localizations with high demand for p97 activity.

According to the Human Protein Atlas and Proteomics DB databases, VCF1 and 2 are broadly expressed in many human tissues, including strong expression in the brain. In this context, it is interesting to note that both proteins have recently been implicated in neurodegenerative diseases (VCF1: amyotrophic lateral sclerosis; VCF2: Alzheimer’s disease), based on systematic yeast two-hybrid screening and computationally predicted neurodegenerative disease-associated protein clusters (Haenig et al., 2020). Moreover, the potential link between VCF1/2 and p97-mediated DNA damage repair suggested by our data could hint to a role of VCF1/2 in p97-dependent cancer cell survival, an area of intense biomedical research efforts. While the exact role of VCF1/2 in the control of nuclear p97 functions remains to be determined, this work provides a starting point for the future exploration of the FAM104 protein family in basic and translational research.

Plasmids, antibodies, and other key resources used in this study are listed in Appendix 1—key resources table.

All data analysed during this study are included in the manuscript and supporting files; Source Data files accompany the respective figures.

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Author details

1. Maria Körner

   University of Würzburg, Biocenter, Chair of Biochemistry I, Würzburg, Germany

   Contribution

   Resources, Investigation, Visualization, Methodology, Writing - review and editing

   Contributed equally with

   Susanne R Meyer

   Competing interests

   No competing interests declared

2. Susanne R Meyer

   University of Würzburg, Biocenter, Chair of Biochemistry I, Würzburg, Germany

   Contribution

   Resources, Investigation

   Contributed equally with

   Maria Körner

   Competing interests

   No competing interests declared

3. Gabriella Marincola

   University of Würzburg, Biocenter, Chair of Biochemistry I, Würzburg, Germany

   Present address

   Labor Dr. Brunner, Konstanz, Germany

   Contribution

   Resources, Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9227-6554

4. Maximilian J Kern

   Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany

   Present address

   Roche Diagnostics GmbH, Penzberg, Germany

   Contribution

   Investigation

   Competing interests

   No competing interests declared

5. Clemens Grimm

   University of Würzburg, Biocenter, Chair of Biochemistry I, Würzburg, Germany

   Contribution

   Visualization

   Competing interests

   No competing interests declared

6. Christina Schuelein-Voelk

   Core Unit High-Content Microscopy, Biocenter, University of Würzburg, Würzburg, Germany

   Contribution

   Resources, Methodology

   Competing interests

   No competing interests declared

7. Utz Fischer

   University of Würzburg, Biocenter, Chair of Biochemistry I, Würzburg, Germany

   Contribution

   Resources

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1465-6591

8. Kay Hofmann

   Institute of Genetics, University of Cologne, Cologne, Germany

   Contribution

   Investigation, Visualization

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2289-9083

9. Alexander Buchberger

   University of Würzburg, Biocenter, Chair of Biochemistry I, Würzburg, Germany

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   alexander.buchberger@uni-wuerzburg.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2836-0820

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