Senatore, Emanuela (2021) CENTROSOMAL TBC1D31 INTEGRATES cAMP SIGNALING AND OFD1 UBIQUITYLATION TO CONTROL CILIOGENESIS. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Resource language: English
Title: CENTROSOMAL TBC1D31 INTEGRATES cAMP SIGNALING AND OFD1 UBIQUITYLATION TO CONTROL CILIOGENESIS
Creators:
CreatorsEmail
Senatore, Emanuelaemanuela.senatore@unina.it
Date: 13 July 2021
Number of Pages: 89
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Dottorato: Medicina molecolare e biotecnologie mediche
Ciclo di dottorato: 33
Coordinatore del Corso di dottorato:
nomeemail
Santoro, Massimomassimo.santoro@unina.it
Tutor:
nomeemail
Feliciello, AntonioUNSPECIFIED
Date: 13 July 2021
Number of Pages: 89
Keywords: ubiquitylation, ciliogenesis, cAMP, phosphorylation, ciliopathies
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/04 - Patologia generale
Date Deposited: 19 Jul 2021 11:00
Last Modified: 07 Jun 2023 10:43
URI: http://www.fedoa.unina.it/id/eprint/13655

Collection description

The primary cilium is a microtubule-based organelle that regulates growth and development. Defects in ciliogenesis can lead to a group of genetic syndromes known as ciliopathies. The Oro-facial digital syndrome 1 (OFD1) is a X-linked ciliopathy caused by mutation in OFD1 gene, whose role in ciliogenesis is well established. Additionally, cAMP and ubiquitin pathway play a role in ciliogenesis. In mammals, most of the effects elicited by cAMP are mediated by protein kinase A (PKA). The cAMP-PKA pathway can induce activation of praja2, a RING E3-ubiquitin ligase of the ubiquitin-proteasome system (UPS). By a yeast two-hybrid screening, we identified TBC1D31 as a novel interactor of praja2. TBC1D31 is a protein localized at the centrosome and basal body, whose function is unknown. Given the role of centrosome in the control of primary cilia formation, the aim of my study was to investigate the role of TBC1D31 in ciliogenesis and evaluate the impact of cAMP and praja2 in TBC1D31-mediated ciliary functions. We identified a scaffold complex assembled by TBC1D31 at centrosome that includes the ubiquitin ligase praja2, protein kinase A (PKA) and OFD1. We show that TBC1D31 is essential for ciliogenesis and for Medaka fish development. Upon cAMP stimulation, PKA phosphorylates OFD1 at ser735. Phosphorylation primes OFD1 to praja2-mediated ubiquitylation and proteasomal degradation. Removal of OFD1 promotes primary cilia resorption. Altogether, our findings indicate that TBC1D31 is a novel centrosomal scaffold protein that physically and functionally links the activation of the cAMP signalling to the regulation of primary cilium biology and development.

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