Primary cilia are antenna-like sensory organelles that play pivotal roles in coordinating various signaling pathways important for human development and tissue homeostasis (Anvarian et al., 2019). They comprise a microtubule-based axoneme core, which extends directly from the mother centriole-derived basal body and is surrounded by a bilayer membrane enriched for specific receptors, ion channels, and lipids that endow the organelle with unique signaling properties (Nachury and Mick, 2019). Not surprisingly, mutations in genes that affect assembly, structure, or function of cilia are causative for a growing number of pleiotropic diseases and syndromes called ciliopathies, which include cone-rod dystrophy in the retina and hearing loss (CRDHL; MIM# 617236) amongst others (Reiter and Leroux, 2017). Ciliopathy genes include those coding for components of the centrosome, which contains the daughter and mother centriole and gives rise to the ciliary basal body. The mother centriole is distinguished from the daughter centriole by distal and subdistal appendages, which play critical roles in vesicle docking at the onset of ciliogenesis and in microtubule anchoring, respectively. In addition, the centrosome contains pericentriolar material and is associated with centriolar satellites that affect cilia biogenesis and function in various ways (Breslow and Holland, 2019).

Assembly of primary cilia is a complex, multistep process that is tightly coordinated with the cell cycle. In actively proliferating cells, centriolar coiled coil protein 110 (CP110; also known as CCP110) and centrosomal protein of 97 kDa (CEP97) cap the distal ends of both mother and daughter centrioles and suppress ciliogenesis. Furthermore, overexpression of CP110 in growth-arrested cells prevents ciliogenesis (Spektor et al., 2007). CP110 also regulates centriole duplication and length control during S phase and interacts with key regulators of centriole duplication, including PLK4 (Chen et al., 2002; Kleylein-Sohn et al., 2007; D'Angiolella et al., 2010; Li et al., 2013). As cells enter G1/G0, ciliogenesis begins with recruitment of pre-ciliary vesicles to the distal end of the mother centriole. The vesicles subsequently fuse to form a larger ciliary vesicle underneath which the ciliary transition zone and axoneme are assembled. The axoneme is further extended by intraflagellar transport (IFT), and the ciliary vesicle expands and matures to form the ciliary membrane and a surrounding sheath that fuses with the plasma membrane upon completion of ciliogenesis (Sorokin, 1962; Sorokin, 1968; Shakya and Westlake, 2021).

Initiation of transition zone formation and axoneme extension during early stages of ciliogenesis require removal of the CEP97-CP110 complex from the distal end of the mother centriole (Spektor et al., 2007). This process relies on M-phase phosphoprotein 9 (MPP9), which interacts directly with CEP97 and cooperates with kinesin KIF24 to recruit the CEP97-CP110 complex to the distal centriole end (Kobayashi et al., 2011; Huang et al., 2018). During ciliogenesis, phosphorylation of MPP9 by Tau tubulin kinase 2 (TTBK2) leads to degradation of MPP9 by the ubiquitin proteasome system (UPS), which results in destabilization of the CEP97-CP110 complex causing its removal from the distal end of the mother centriole (Huang et al., 2018). TTBK2 is recruited to the mother centriole distal appendages by CEP164 (Čajánek and Nigg, 2014; Oda et al., 2014), where it also phosphorylates CEP83 to promote CP110 removal (Lo et al., 2019). Consequently, depletion of CEP164, TTBK2, CEP83, or other centriole distal appendage proteins that regulate their localization and/or function impairs ciliogenesis (Graser et al., 2007; Goetz et al., 2012; Schmidt et al., 2012; Tanos et al., 2013; Ye et al., 2014; Kurtulmus et al., 2018). Mother centriole recruitment of TTBK2 and removal of the distal CEP97-CP110 cap additionally require the subdistal CEP350-FOP-CEP19 complex, which furthermore interacts with RABL2 and IFT-B complex components to promote their axonemal entry (Kanie et al., 2017; Nishijima et al., 2017; Mojarad et al., 2017).

Despite recent advances, the precise mechanisms by which CP110 regulates ciliogenesis and is removed from the mother centriole at the onset of ciliogenesis remain incompletely understood. For example, a recent study implicated the homologous to the E6AP carboxyl terminus (HECT)-type EDD1-DYRK2-DDB1^VPRBP E3 ligase complex in ubiquitination and degradation of CP110 via a mechanism involving direct interaction of viral protein R binding protein (VPRBP; also known as DCAF1) and centrosomal protein of 78 kDa (CEP78) (Hossain et al., 2017). Specifically, the authors reported that CEP78 suppresses CP110 ubiquitination by EDD1 (also known as UBR5 and EDD), and it was proposed that CP110 is phosphorylated by DYRK2 and thereby recognized and brought close to EDD1 by VPRBP. EDD1 then transfers ubiquitin to CP110, leading to its degradation. When CEP78 binds VPRBP, it induces a conformational change in the complex, thereby preventing CP110 ubiquitination. Further, they demonstrated that depletion of CEP78 promoted centriole elongation, whereas CEP78 overexpression inhibited primary cilia formation in hTERT-immortalized retinal pigment epithelial (RPE1) cells (Hossain et al., 2017). On the other hand, knockout (KO) of Dyrk2 in the mouse was reported to result in elongation of primary cilia, but centrosomal CP110 levels appeared unaffected in Dyrk2 mouse KO cells (Yoshida et al., 2020). Therefore, it remains uncertain how CEP78 and the EDD1-DYRK2-DDB1^VPRBP complex affect CP110 homeostasis to control ciliogenesis.

CEP78 is composed of 16 exons and encodes a protein comprising 722 amino acids that possesses five consecutive leucine-rich repeats (LRR) at the N-terminus and a coiled-coil (CC) domain at the C-terminus (Nikopoulos et al., 2016; Ascari et al., 2020). Four independent studies have reported eight different mutations in CEP78 in patients with CRDHL (Nikopoulos et al., 2016; Ascari et al., 2020; Namburi et al., 2016; Fu et al., 2017), whereas one study identified a homozygous CEP78-truncating variant in a family with non-syndromic retinitis pigmentosa (MIM# 268003; de Castro-Miró et al., 2016), another form of retinal degeneration. Of these studies, two have investigated the functional consequences of human CEP78 mutations at the cellular level. In one study, whole-exome sequencing (WES) identified biallelic mutations in CEP78 in two unrelated families from Greece and Sweden, respectively (Nikopoulos et al., 2016). The Greek subject had a homozygous base substitution at the splice donor site in intron 3 of CEP78 (NM_032171.2:c.499+1G>T). Two subjects from a Swedish family carried heterozygous mutations, one base substitution in intron 3 (NM_032171.2:c.499+5G>A) and a single-nucleotide deletion in exon 5 (NM_032171.2:c.633del; p.Trp212GlyfsTer18) causing a frameshift. These CEP78 mutations lead to exon skipping and premature stop codons accompanied by almost undetectable levels of CEP78 protein in human skin fibroblasts (HSFs) of affected individuals. Furthermore, it was found that HSFs from these patients have significantly longer primary cilia as compared to control cells (Nikopoulos et al., 2016). More recently, a missense mutation in CEP78 (NM_032171.2:c.449T>C; p.Leu150Ser) was identified in three unrelated families from Belgium and Germany diagnosed with CRDHL (Ascari et al., 2020). In the two Belgian families, affected individuals were homozygous for the p.Leu150Ser variant, whereas affected individuals from the German family displayed compound heterozygosity for this variant and a novel splice site variant, NM_032171.2:c.1462–1G>T. In all cases, HSFs from patients harboring the p.Leu150Ser mutation (hereafter: L150S) displayed decreased cellular levels of CEP78 and significantly elongated cilia compared to control HSFs (Ascari et al., 2020), as seen in patient-derived HSFs with CEP78 truncating mutations (Nikopoulos et al., 2016). In addition, other ciliopathy features were reported in some of the affected individuals with the CEP78^L150S mutation, including obesity, respiratory problems, diabetes 2, and infertility (Ascari et al., 2020). In summary, available data derived from human patients indicates that depletion of CEP78 leads to elongation of primary cilia at the cellular level, which manifests in ciliopathy phenotypes at the organism level. However, the mechanism by which CEP78 regulates ciliary length is not known.

In addition to the patient studies described above, some studies have addressed CEP78 function in different cell culture models. First, a study showed that siRNA-mediated depletion of CEP78 in RPE1 cells reduces the frequency of cells forming primary cilia, possibly due to centriolar anchoring defects, but the length of the residual cilia was not assessed. Similarly, depletion of CEP78 in Planarians was shown to impair motile cilia formation due to defective docking of centrioles to the cell surface (Azimzadeh et al., 2012). Another study identified CEP78 interaction with PLK4 and implicated CEP78 in PLK4-mediated centriole over duplication, whereas possible roles for CEP78 in relation to cilia were not addressed (Brunk et al., 2016). Finally, as mentioned above, a study reported that CEP78 directly interacts with VPRBP of the EDD1-DYRK2-DDB1^VPRBP E3 ligase complex to suppress CP110 ubiquitination and thereby stabilize it (Hossain et al., 2017). How such CEP78-mediated stabilization of CP110 might lead to the long cilia phenotype observed in patient fibroblasts lacking CEP78 (Nikopoulos et al., 2016; Ascari et al., 2020) and/or the reduced ciliation frequencies seen in CEP78-depleted Planarians and RPE1 cells (Azimzadeh et al., 2012) is unclear.

Here, we show that in RPE1 cells and patient-derived HSFs loss of CEP78 leads to reduced ciliation frequency as well as increased length of the cilia that do form. Further, we find that a mutant line expressing a partially functional, truncated version of CEP78 displays reduced ciliation frequency but normal length of residual cilia. By taking advantage of the recently identified disease-causing CEP78^L150S mutation (Ascari et al., 2020), we used a quantitative mass spectrometry-based approach to identify a disease-relevant interactome of CEP78. We confirmed that CEP78 interacts with the EDD1-DYRK2-DDB1^VPRBP complex implicated in CP110 ubiquitination and degradation (Hossain et al., 2017), and furthermore identified a novel interaction between CEP78 and the N-terminal region of CEP350. The interaction of CEP78 with both VPRBP and CEP350, as well as centrosomal recruitment of CEP78, is dramatically reduced by the CEP78^L150S mutation. Lack of centrosomal recruitment of CEP78^L150S is likely due to impaired interaction with CEP350 since centrosomal and cellular levels of CEP78 were significantly decreased in CEP350 KO cells. Conversely, cells lacking CEP78 displayed significantly decreased centrosomal levels of EDD1 and unaltered or slightly increased centrosomal levels of VPRBP and CEP350. In addition, CEP78-deficient cells showed significantly increased cellular and centrosomal levels of CP110, presumably owing to the reduced centrosomal levels of EDD1 observed in these cells. Depletion of CP110 in CEP78-deficient cells restored ciliation frequency, but not the increased length of remaining cilia, to normal. Collectively our results suggest that CEP78 functions downstream of CEP350 to promote cilia biogenesis by negatively regulating CP110 levels via an EDD1-dependent mechanism, but suppresses ciliary elongation independently of CP110.

Several studies have shown that loss-of-function mutations in CEP78 are causative of ciliopathy characterized by CRDHL (Nikopoulos et al., 2016; Ascari et al., 2020; Namburi et al., 2016; Fu et al., 2017), and that cells lacking CEP78 display reduced ciliation frequency (Azimzadeh et al., 2012) or abnormally long cilia (Nikopoulos et al., 2016; Ascari et al., 2020). However, the molecular mechanisms by which CEP78 regulates cilium biogenesis and length were so far unclear. In this study, we found that loss of CEP78 leads to decreased ciliation frequency as well as increased length of the residual cilia that do form, both in RPE1 cells and patient-derived HSFs. Rescue experiments in CEP78 KO RPE1 cells stably expressing mNG-CEP78 or mNG-CEP78^L150 supported that the observed phenotypes were specifically caused by loss of CEP78 at the centrosomes. Interestingly, we found that both ciliated and non-ciliated CEP78-deficient cells fail to efficiently recruit EDD1 to the centrosome, whereas cellular and overall centrosomal levels of CP110 are dramatically increased. However, in the subpopulation of CEP78 KO cells that are ciliated, CP110 levels specifically at the mother centriole were similar to those of ciliated control cells, implying that the elevated centrosomal CP110 level observed in these cells is caused by a pool of CP110 located at the daughter centriole and/or pericentriolar area. This result also indicates that the abnormally long cilia phenotype seen in the CEP78 KO cells is not caused by increased CP110 levels at the mother centriole. Supportively, siRNA-mediated depletion of CP110 could restore cilia frequency, but not length, to normal in the CEP78 KO cells. Furthermore, a CEP78 mutant line, clone #44, expressing a shorter version of CEP78 likely lacking the N-terminus displayed reduced ciliation frequency but normal length of residual cilia, substantiating that CEP78 regulates ciliogenesis and cilia length by distinct mechanisms. Specifically, our results indicate that CEP78 promotes ciliogenesis by negatively regulating CP110 levels at the mother centriole via activation of VprBP, but negatively regulates ciliary lengthening independently of CP110 (Figure 8F).

The removal of CP110 from the distal end of the mother centriole constitutes a key step in the initiation of ciliogenesis and is regulated by a growing number of proteins that include TTBK2 (Goetz et al., 2012) and components of the UPS system such as Neurl-4 (Loukil et al., 2017) and the cullin-3 (CUL3)–RBX1–KCTD10 complex (Nagai et al., 2018). The EDD1-DYRK2-DDB1^VPRBP complex was similarly shown to mediate degradation of CP110 and to interact with CEP78 (Hossain et al., 2017), but the precise consequences of these activities for ciliogenesis were unclear. Our work strongly suggests that CEP78 functions together with the EDD1-DYRK2-DDB1^VPRBP complex to negatively regulate centrosomal CP110 levels at the onset of ciliogenesis, leading to its removal from the distal end of the mother centriole (Figure 8F). This is in contrast to a previously proposed model, which suggested that CEP78 inhibits degradation of CP110 by the EDD1-DYRK2-DDB1^VPRBP complex (Hossain et al., 2017). The reason for this discrepancy is unclear, but may be due to different experimental approaches used in our study and the paper by Hossain et al., 2017. In this latter study, siRNA was used to partially deplete CEP78 from cultured cells, whereas we performed our experiments on cells with endogenous CEP78 mutations. CP110 removal from the distal end of the mother centriole occurs concomitantly with docking of the centriole to vesicles or the plasma membrane at the onset of ciliogenesis (Shakya and Westlake, 2021). Therefore, a role for CEP78 in removal of CP110 from the centrosome is compatible with ultrastructural analyses in Planarians, which indicated that basal bodies fail to dock to the plasma membrane in CEP78 RNAi-depleted animals (Azimzadeh et al., 2012). Although not addressed in detail in the current study, the elevated centrosomal CP110 levels observed in serum-fed CEP78-deficient cells are also compatible with previous work implicating CEP78 in regulation of PLK4-mediated centriole duplication (Brunk et al., 2016).

We also uncovered a new physical interaction between CEP78 and the N-terminal region of CEP350 and found that CEP350 is important for recruitment of CEP78 to the centrosome as well as for its overall stability. The reduced interaction of the CEP78^L150S mutant protein with CEP350 might explain its lack of detection by western blot analysis of patient HSFs (Ascari et al., 2020) since reduced interaction with CEP350 is likely to decrease the long-term stability of CEP78^L150S. Our IP and IFM results furthermore suggest that CEP350 controls CP110 removal from the mother centriole not only via recruitment of TTBK2 (Kanie et al., 2017), but also via CEP78-dependent recruitment of EDD1. Indeed, we observed reduced centrosomal levels of EDD1 in CEP350 KO cells, consistent with this idea. It remains to be determined whether these two pathways act in sequence or in parallel to control centrosomal CP110 levels. Furthermore, as the recruitment of CEP350 to centrioles itself depends on FOP (Kanie et al., 2017; Mojarad et al., 2017; Yan et al., 2006) and on the distal centriole protein C2CD3 (Huang et al., 2018), loss of these proteins may similarly affect the centrosomal recruitment of CEP78 and EDD1, and thereby negatively regulate CP110 levels via this pathway. It will be important to investigate these possibilities in future studies.

While increased CP110 levels can account for the decreased ciliation frequency observed in serum-deprived CEP78 mutant cells, it remains unclear why some of these cells form abnormally long cilia. Our analysis indicated that the ciliated mutant cells are able to locally displace or degrade CP110 at the mother centriole, but the underlying mechanism remains to be determined. Of note, the CEP350 KO cells used in our study also seem to display a similar dual phenotype since approximately 30% of these cells form cilia despite an inability to recruit TTBK2 and remove CP110 from the mother centriole (Kanie et al., 2017). Moreover, a recent genome-wide siRNA knockdown analysis showed that depletion of DDB1 caused an elongated cilia phenotype, whereas depletion of EDD1 (UBR5) leads to fewer but normal length cilia (Wheway et al., 2015), even though DDB1 and EDD1 are part of the same E3 ubiquitin ligase complex (Nakagawa et al., 2013). Thus, a slight imbalance in the regulation of this complex might determine whether or not cilia are formed and how long they are. It should also be noted that some studies have reported dual roles for CP110 during ciliogenesis, that is, CP110 may not only function to inhibit ciliogenesis but may also promote ciliary extension in some contexts (Yadav et al., 2016; Walentek et al., 2016). Although the mechanism responsible for the elongated cilia phenotype seen in some of the CEP78 mutant cells remains unclear, one attractive candidate to be involved is CEP350, which we found to be present at abnormally high levels at the centrosome of ciliated CEP78 KO cells, specifically. Consistent with this idea, we have observed that the CEP78 truncation mutant (clone #44), which expresses fewer, but normal length cilia, displays normal or slightly reduced levels of CEP350 at the centrosome in ciliated as well as in non-ciliated cells (data not shown). Alternatively, one or more substrates of EDD1 other than CP110 could also be affected in the CEP78 mutant cells, thereby affecting ciliary length control. For example, EDD1 was also shown to mediate ubiquitination of CSPP-L in turn promoting its recruitment to centriolar satellites and the centrosome (Shearer et al., 2018). CSPP-L is a well-known positive regulator of primary cilia formation (Patzke et al., 2010) that was recently shown to bind directly to CEP104 to control axoneme extension (Frikstad et al., 2019). Furthermore, CEP104 is implicated in ciliogenesis through interaction with the CEP97-CP110 complex and modulation of microtubule dynamics at the ciliary tip (Frikstad et al., 2019; Jiang et al., 2012; Satish Tammana et al., 2013). It will therefore be interesting to investigate if and how CSPP-L and CEP104 localization is affected in CEP78 mutant cells. Moreover, as CEP350 additionally binds to CYLD (Eguether et al., 2014), a deubiquitinase that controls centriolar satellite homeostasis and ciliogenesis through de-ubiquitination of the E3 ubiquitin ligase MIB1 (Wang et al., 2016; Douanne et al., 2019), and was proposed to regulate axonemal IFT particle injection through FOP-CEP19-RABL2 interactions (Kanie et al., 2017; Nishijima et al., 2017; Mojarad et al., 2017), it is tempting to speculate that CEP78 might impinge on these processes.

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 3A and Figure 7-figure supplement 2.

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Author details

1. André Brás Gonçalves

   Department of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark

   Present address

   Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

   Contribution

   Conceptualization, Formal analysis, Supervision, Investigation, Visualization, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

2. Sarah Kirstine Hasselbalch

   Department of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark

   Contribution

   Formal analysis, Investigation, Methodology, Writing - original draft

   Contributed equally with

   Beinta Biskopstø Joensen

   Competing interests

   No competing interests declared

3. Beinta Biskopstø Joensen

   Department of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark

   Contribution

   Conceptualization, Formal analysis, Supervision, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Sarah Kirstine Hasselbalch

   Competing interests

   No competing interests declared

4. Sebastian Patzke

   Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

   Contribution

   Formal analysis, Visualization, Writing - review and editing

   Competing interests

   No competing interests declared

5. Pernille Martens

   Department of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark

   Contribution

   Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

6. Signe Krogh Ohlsen

   Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

   Contribution

   Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

7. Mathieu Quinodoz

   1. Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland
   2. Department of Ophthalmology, University of Basel, Basel, Switzerland
   3. Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom

   Contribution

   Formal analysis, Investigation, Visualization, Methodology

   Competing interests

   No competing interests declared

8. Konstantinos Nikopoulos

   Department of Computational Biology, University of Lausanne, Lausanne, Switzerland

   Contribution

   Formal analysis, Investigation, Visualization, Methodology

   Competing interests

   No competing interests declared

9. Reem Suleiman

   Department of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark

   Contribution

   Investigation

   Competing interests

   No competing interests declared

10. Magnus Per Damsø Jeppesen

    Department of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark

    Contribution

    Investigation, Methodology

    Competing interests

    No competing interests declared

11. Catja Weiss

    Department of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark

    Contribution

    Investigation, Methodology

    Competing interests

    No competing interests declared

12. Søren Tvorup Christensen

    Department of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark

    Contribution

    Investigation, Methodology, Writing - review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-5004-304X

13. Carlo Rivolta

    1. Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland
    2. Department of Ophthalmology, University of Basel, Basel, Switzerland
    3. Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom

    Contribution

    Formal analysis, Supervision, Funding acquisition, Visualization, Writing - original draft, Project administration, Writing - review and editing

    Competing interests

    No competing interests declared

14. Jens S Andersen

    Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

    Contribution

    Formal analysis, Supervision, Funding acquisition, Visualization, Writing - original draft, Project administration, Writing - review and editing

    Competing interests

    No competing interests declared

15. Pietro Farinelli

    Department of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark

    Contribution

    Conceptualization, Formal analysis, Supervision, Funding acquisition, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

    For correspondence

    Pietro.Farinelli@twelve.bio

    Competing interests

    No competing interests declared

16. Lotte Bang Pedersen

    Department of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark

    Contribution

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

    For correspondence

    lbpedersen@bio.ku.dk

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-9749-3758

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