The E3 ubiquitin ligase UBR5 regulates centriolar satellite stability and primary cilia
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.
|ISBN||1939-4586 (Electronic) 1059-1524 (Linking)|
|Authors||Shearer, R. F.; Frikstad, K. M.; McKenna, J.; McCloy, R. A.; Deng, N.; Burgess, A.; Stokke, T.; Patzke, S.; Saunders, D. N.|
|Responsible Garvan Author||Rachael Zekanovic|
|Publisher Name||MOLECULAR BIOLOGY OF THE CELL|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/29742019|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/14692|