Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12.
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Date
2021-04-06ICR Author
Author
Khan, OM
Almagro, J
Nelson, JK
Horswell, S
Encheva, V
Keyan, KS
Clurman, BE
Snijders, AP
Behrens, A
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
HCT116 Cells
Humans
Proteasome Endopeptidase Complex
Ubiquitin-Conjugating Enzymes
Ubiquitin-Protein Ligases
Lysine
Carrier Proteins
RNA, Small Interfering
Protein Processing, Post-Translational
Protein Binding
Substrate Specificity
Drug Resistance, Neoplasm
Ubiquitination
Biocatalysis
Protein Stability
HEK293 Cells
Proteolysis
Myeloid Cell Leukemia Sequence 1 Protein
F-Box-WD Repeat-Containing Protein 7
Language
eng
Date accepted
2021-03-03
License start date
2021-04-06
Citation
Nature communications, 2021, 12 (1), pp. 2043 - ?
Publisher
NATURE RESEARCH
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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