USP9X counteracts differential ubiquitination of NPHP5 by MARCH7 and BBS11 to regulate ciliogenesis

PLoS Genetics
Arindam DasWilliam Y Tsang

Abstract

Ciliogenesis is a fundamental biological process central to human health. Precisely how this process is coordinated with the cell cycle remains an open question. We report that nephrocystin-5 (NPHP5/IQCB1), a positive regulator of ciliogenesis, is a stable and low turnover protein subjected to cycles of ubiquitination and deubiquitination. NPHP5 directly binds to a deubiquitinating enzyme USP9X/FAM and two E3 ubiquitin ligases BBS11/TRIM32 and MARCH7/axotrophin. NPHP5 undergoes K63 ubiquitination in a cell cycle dependent manner and K48/K63 ubiquitination upon USP9X depletion or inhibition. In the G0/G1/S phase, a pool of cytoplasmic USP9X recruited to the centrosome by NPHP5 protects NPHP5 from ubiquitination, thus favouring cilia assembly. In the G2/M phase, USP9X dissociation from the centrosome allows BBS11 to K63 ubiquitinate NPHP5 which triggers protein delocalization and loss of cilia. BBS11 is a resident centrosomal protein, whereas cytoplasmic USP9X sequesters the majority of MARCH7 away from the centrosome during interphase. Depletion or inhibition of USP9X leads to an accumulation of centrosomal MARCH7 which K48 ubiquitinates NPHP5, triggering protein degradation and cilia loss. At the same time, BBS11 K63 ubiquitina...Continue Reading

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Citations

May 5, 2018·The Journal of Biological Chemistry·Delowar HossainWilliam Y Tsang
Sep 14, 2017·Biochemical Society Transactions·Sarah DarlingJudy M Coulson
Jun 10, 2019·Cellular and Molecular Life Sciences : CMLS·Delowar HossainWilliam Y Tsang
Jun 6, 2020·Journal of Cell Science·Tiffany Yu, Miho Matsuda
Aug 23, 2020·International Journal of Molecular Sciences·Takashi ShiromizuYuhei Nishimura
Jan 5, 2021·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Yuhei Nishimura, Masaki Inagaki
Dec 19, 2020·Cell Death and Differentiation·Mohammed A BasarAchim Werner
Nov 12, 2021·Biomedical Reports·Ina Ofelia FocșaMihaela Bălgrădean

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Methods Mentioned

BETA
polyubiquitination
ubiquitination
deubiquitination
co-immunoprecipitation
immunoprecipitations
immunoprecipitation
Fluorescence-activated cell sorting
transfection
PCR
electrophoresis

Software Mentioned

Qual Browser / Xcalibur
ImageJ

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