title: SDCCAG8 Interacts with RAB Effector Proteins RABEP2 and ERC1 and Is Required for Hedgehog Signaling.
abstract: Recessive mutations in the SDCCAG8 gene cause a nephronophthisis-related ciliopathy with Bardet-Biedl syndrome-like features in humans. Our previous characterization of the orthologous Sdccag8gt/gt mouse model recapitulated the retinal-renal disease phenotypes and identified impaired DNA damage response signaling as an underlying disease mechanism in the kidney. However, several other phenotypic and mechanistic features of Sdccag8gt/gt mice remained unexplored. Here we show that Sdccag8gt/gt mice exhibit developmental and structural abnormalities of the skeleton and limbs, suggesting impaired Hedgehog (Hh) signaling. Indeed, cell culture studies demonstrate the requirement of SDCCAG8 for ciliogenesis and Hh signaling. Using an affinity proteomics approach, we demonstrate that SDCCAG8 interacts with proteins of the centriolar satellites (OFD1, AZI1), of the endosomal sorting complex (RABEP2, ERC1), and with non-muscle myosin motor proteins (MYH9, MYH10, MYH14) at the centrosome. Furthermore, we show that RABEP2 localization at the centrosome is regulated by SDCCAG8. siRNA mediated RABEP2 knockdown in hTERT-RPE1 cells leads to defective ciliogenesis, indicating a critical role for RABEP2 in this process. Together, this study identifies several centrosome-associated proteins as novel SDCCAG8 interaction partners, and provides new insights into the function of SDCCAG8 at this structure.
authors.affiliation: Department of Medicine, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Rannar
authors.identifier: 0000-0002-7055-6325
authors.initials: R
authors.lastname: Airik
authors.affiliation: Department of Medicine, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Markus
authors.initials: M
authors.lastname: Schueler
authors.affiliation: Department of Medicine, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Merlin
authors.initials: M
authors.lastname: Airik
authors.affiliation: Department of Medicine, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Jang
authors.initials: J
authors.lastname: Cho
authors.affiliation: Department of Pediatrics, Division of Nephrology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Kelsey A
authors.initials: KA
authors.lastname: Ulanowicz
authors.affiliation: Department of Medicine, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Porath
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Toby W
authors.initials: TW
authors.lastname: Hurd
authors.affiliation: NNF Center for Protein Research, University of Copenhagen, Faculty of Health Sciences, Copenhagen, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Bekker-Jensen
authors.affiliation: Department of Biochemistry and Molecular Biology; University of Southern Denmark, Odense M, Denmark.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Schrøder
authors.affiliation: Department of Biochemistry and Molecular Biology; University of Southern Denmark, Odense M, Denmark.
authors.forename: Jens S
authors.initials: JS
authors.lastname: Andersen
authors.affiliation: Department of Medicine, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts, United States of America.|Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D002502:Centrioles / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001324:Autoantigens; D053823:Hedgehog Proteins; D009363:Neoplasm Proteins; C472381:Sdccag8 protein, mouse; D033921:Vesicular Transport Proteins; D009218:Myosins