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Mol Biol Cell. 2018 Jul 1;29(13):1542-1554. doi: 10.1091/mbc.E17-04-0248. Epub 2018 May 9.

The E3 ubiquitin ligase UBR5 regulates centriolar satellite stability and primary cilia.

Author information

1
Garvan Institute of Medical Research, Kinghorn Cancer Centre, Darlinghurst 2010, Australia.
2
Faculty of Medicine, St. Vincent's Clinical School, University of New South Wales, Sydney 2052, Australia.
3
Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway.
4
Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney 2052, Australia.

Abstract

Primary cilia are crucial for signal transduction in a variety of pathways, including hedgehog and Wnt. Disruption of primary cilia formation (ciliogenesis) is linked to numerous developmental disorders (known as ciliopathies) and diseases, including cancer. The ubiquitin-proteasome system (UPS) component UBR5 was previously identified as a putative positive regulator of ciliogenesis in a functional genomics screen. UBR5 is an E3 ubiquitin ligase that is frequently deregulated in tumors, but its biological role in cancer is largely uncharacterized, partly due to a lack of understanding of interacting proteins and pathways. We validated the effect of UBR5 depletion on primary cilia formation using a robust model of ciliogenesis, and identified CSPP1, a centrosomal and ciliary protein required for cilia formation, as a UBR5-interacting protein. We show that UBR5 ubiquitylates CSPP1, and that UBR5 is required for cytoplasmic organization of CSPP1-comprising centriolar satellites in centrosomal periphery, suggesting that UBR5-mediated ubiquitylation of CSPP1 or associated centriolar satellite constituents is one underlying requirement for cilia expression. Hence, we have established a key role for UBR5 in ciliogenesis that may have important implications in understanding cancer pathophysiology.

PMID:
29742019
PMCID:
PMC6080653
DOI:
10.1091/mbc.E17-04-0248
[Indexed for MEDLINE]
Free PMC Article

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