The TBC1D31/praja2 complex controls primary ciliogenesis through PKA-directed OFD1 ubiquitylation(166 views)(PDF restricted38 views) Senatore E, Chiuso F, Rinaldi L, Intartaglia D, Donne RD, Pedone E, Catalanotti B, Pirone L, Fiorillo B, Moraca F, Giamundo G, Scala G, Raffeiner A, Torres-quesada O, Stefan E, Kwiatkowski M, Pijkeren A, Morleo M, Franco B, Garbi C, Conte I, Feliciello A
Embo J (ISSN: 0261-4189linking), 2021 May 17; 40(10): e106503-N/D.
Department of Molecular Medicine and Medical Biotechnologies, University Federico II, Naples, Italy.
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
Institute of Biostructures and Bioimaging, CNR, Naples, Italy.
Department of Pharmacy, University Federico II, Naples, Italy.
Net4Science srl, University "Magna Graecia", Catanzaro, Italy.
Department of Biology, University Federico II, Naples, Italy.
Institute of Biochemistry, University of Innsbruck, Innsbruck, Austria.
Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.
Tyrolean Cancer Research Institute, Innsbruck, Austria.
Department of Translational Medical Science, University Federico II, Naples, Italy.
References: Not available.
The TBC1D31/praja2 complex controls primary ciliogenesis through PKA-directed OFD1 ubiquitylation
The primary cilium is a microtubule-based sensory organelle that dynamically links signalling pathways to cell differentiation, growth, and development. Genetic defects of primary cilia are responsible for genetic disorders known as ciliopathies. Orofacial digital type I syndrome (OFDI) is an X-linked congenital ciliopathy caused by mutations in the OFD1 gene and characterized by malformations of the face, oral cavity, digits and, in the majority of cases, polycystic kidney disease. OFD1 plays a key role in cilium biogenesis. However, the impact of signalling pathways and the role of the ubiquitin-proteasome system (UPS) in the control of OFD1 stability remain unknown. Here, we identify a novel complex assembled at centrosomes by TBC1D31, including the E3 ubiquitin ligase praja2, protein kinase A (PKA), and OFD1. We show that TBC1D31 is essential for ciliogenesis. Mechanistically, upon G-protein-coupled receptor (GPCR)-cAMP stimulation, PKA phosphorylates OFD1 at ser735, thus promoting OFD1 proteolysis through the praja2-UPS circuitry. This pathway is essential for ciliogenesis. In addition, a non-phosphorylatable OFD1 mutant dramatically affects cilium morphology and dynamics. Consistent with a role of the TBC1D31/praja2/OFD1 axis in ciliogenesis, alteration of this molecular network impairs ciliogenesis in vivo in Medaka fish, resulting in developmental defects. Our findings reveal a multifunctional transduction unit at the centrosome that links GPCR signalling to ubiquitylation and proteolysis of the ciliopathy protein OFD1, with important implications on cilium biology and development. Derangement of this control mechanism may underpin human genetic disorders.
The TBC1D31/praja2 complex controls primary ciliogenesis through PKA-directed OFD1 ubiquitylation
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The TBC1D31/praja2 complex controls primary ciliogenesis through PKA-directed OFD1 ubiquitylation