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.

Comparative Transcriptomics of Alternative Developmental Phenotypes in a Marine Gastropod

“…Some of the most differentially expressed transcripts (fold‐change > 64×, P < 0.0001) can be linked to ribosomal processes, such as nucleolin (Tajrishi et al., ). A number of transcripts were identified as members of conserved signal transduction pathways, including neurobeachin, a protein kinase A, which in Drosophila interacts with both notch and egfr (Shamloula et al., ); Wnt signalling associated transcript, Tankyrase‐1 (Huang et al., ); interleukin‐1 receptor‐associated kinase 3, which is part of the Toll receptor pathway and is involved in signal transduction (Wesche et al., ); Rho GTPase‐activating protein 29 (Saras et al., ); and regulatory‐associated protein of mTOR, which is involved in controlling cell growth and mediating cellular response to nutritional levels (Kim et al., ), and has also been linked to ciliogenesis (Cardenas‐Rodriguez et al., ). Downstream translational activators were also highly expressed in nutritive embryos, including transcripts of La‐related protein, which is also part of the mTOR pathway and has been associated with cell division and apoptosis (Burrows et al., ).…”

Bardet–Biedl syndrome: Is it only cilia dysfunction?

“…At least part of the role of CCDC28B in ciliogenesis is mediated by its interaction with SIN1, a member of the mTORC2, albeit independently of this complex. CCDC28B is a coiled-coil protein that in the context of mTORC2 plays a role mediating complex assembly [78]. Thus, it will be interesting to study whether this protein and SIN1 participate in the assembly or function of the BBSome as part of its role in ciliogenesis.…”

Bardet–Biedl syndrome: Genetics, molecular pathophysiology, and disease management

“…Rescue of the kidney cysts upon treating the BBS mutant embryos with mTOR signaling inhibitor rapamycin is being observed in zebrafish models. [60] BBS proteins (BBS1, -2, -4, and -7) interact with proteins present in the kidney. In BBS patients with near normal kidney function without renal cysts and urinary concentration defect, the renal cells lacked cilia and showed normal cell cycle and inactive intracellular machinery for water absorption.…”