Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12

Omar M. Khan (), Jorge Almagro, Jessica K. Nelson, Stuart Horswell, Vesela Encheva, Kripa S. Keyan, Bruce E. Clurman, Ambrosius P. Snijders and Axel Behrens ()
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Omar M. Khan: Adult Stem Cell Laboratory, The Francis Crick Institute
Jorge Almagro: Adult Stem Cell Laboratory, The Francis Crick Institute
Jessica K. Nelson: Adult Stem Cell Laboratory, The Francis Crick Institute
Stuart Horswell: Bioinformatics and Biostatistics
Vesela Encheva: Proteomics, The Francis Crick Institute
Kripa S. Keyan: Hamad Bin Khalifa University, College of Health and Life Sciences Qatar Foundation, Education City
Bruce E. Clurman: Fred Hutchinson Cancer Research Center
Ambrosius P. Snijders: Proteomics, The Francis Crick Institute
Axel Behrens: Adult Stem Cell Laboratory, The Francis Crick Institute

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract The tumour suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), that targets several oncoproteins for proteasomal degradation. FBW7 is widely mutated and FBW7 protein levels are commonly downregulated in cancer. Here, using an shRNA library screen, we identify the HECT-domain E3 ubiquitin ligase TRIP12 as a negative regulator of FBW7 stability. We find that SCFFBW7-mediated ubiquitylation of FBW7 occurs preferentially on K404 and K412, but is not sufficient for its proteasomal degradation, and in addition requires TRIP12-mediated branched K11-linked ubiquitylation. TRIP12 inactivation causes FBW7 protein accumulation and increased proteasomal degradation of the SCFFBW7 substrate Myeloid Leukemia 1 (MCL1), and sensitizes cancer cells to anti-tubulin chemotherapy. Concomitant FBW7 inactivation rescues the effects of TRIP12 deficiency, confirming FBW7 as an essential mediator of TRIP12 function. This work reveals an unexpected complexity of FBW7 ubiquitylation, and highlights branched ubiquitylation as an important signalling mechanism regulating protein stability.

Date: 2021
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DOI: 10.1038/s41467-021-22319-5

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