title: The Bardet-Biedl syndrome-related protein CCDC28B modulates mTORC2 function and interacts with SIN1 to control cilia length independently of the mTOR complex.
abstract: CCDC28B encodes a coiled coil domain-containing protein involved in ciliogenesis that was originally identified as a second site modifier of the ciliopathy Bardet-Biedl syndrome. We have previously shown that the depletion of CCDC28B leads to shortened cilia; however, the mechanism underlying how this protein controls ciliary length is unknown. Here, we show that CCDC28B interacts with SIN1, a component of the mTOR complex 2 (mTORC2), and that this interaction is important both in the context of mTOR signaling and in a hitherto unknown, mTORC-independent role of SIN1 in cilia biology. We show that CCDC28B is a positive regulator of mTORC2, participating in its assembly/stability and modulating its activity, while not affecting mTORC1 function. Further, we show that Ccdc28b regulates cilia length in vivo, at least in part, through its interaction with Sin1. Importantly, depletion of Rictor, another core component of mTORC2, does not result in shortened cilia. Taken together, our findings implicate CCDC28B in the regulation of mTORC2, and uncover a novel function of SIN1 regulating cilia length that is likely independent of mTOR signaling.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Cardenas-Rodriguez
authors.forename: Florencia
authors.initials: F
authors.lastname: Irigoín
authors.forename: Daniel P S
authors.initials: DP
authors.lastname: Osborn
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gascue
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.forename: Jose L
authors.initials: JL
authors.lastname: Badano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002923:Cilia / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes / Q000378:metabolism*; D041681:NIH 3T3 Cells; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D000076225:Mechanistic Target of Rapamycin Complex 2; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases; D029961:Zebrafish Proteins; C507668:CCDC28B protein, human; C587913:CCDC28B protein, mouse; C493277:MAPKAP1 protein, human; C492571:RICTOR protein, human; C525637:rictor protein, mouse; C561937:Mapkap1 protein, mouse