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

Author

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  • Omar M. Khan

    (Adult Stem Cell Laboratory, The Francis Crick Institute
    Hamad Bin Khalifa University, College of Health and Life Sciences Qatar Foundation, Education City)

  • 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
    Cancer Stem Cell Laboratory, Institute of Cancer Research
    Division of Cancer, Department of Surgery and Cancer, Imperial College London
    Convergence Science Centre, Imperial College London)

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.

Suggested Citation

  • Omar M. Khan & Jorge Almagro & Jessica K. Nelson & Stuart Horswell & Vesela Encheva & Kripa S. Keyan & Bruce E. Clurman & Ambrosius P. Snijders & Axel Behrens, 2021. "Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22319-5
    DOI: 10.1038/s41467-021-22319-5
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