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

Autor: Kripa S. Keyan, Jorge Almagro, Bruce E. Clurman, Ambrosius P. Snijders, Stuart Horswell, Vesela Encheva, Jessica K. Nelson, Axel Behrens, Omar M. Khan
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
F-Box-WD Repeat-Containing Protein 7
Ubiquitylation
General Physics and Astronomy
Plasma protein binding
Substrate Specificity
law.invention
Small hairpin RNA
0302 clinical medicine
Ubiquitin
law
MCL1
RNA
Small Interfering
Multidisciplinary
biology
Protein Stability
Chemistry
3. Good health
Ubiquitin ligase
Cell biology
Cancer therapeutic resistance
030220 oncology & carcinogenesis
Protein Binding
Proteasome Endopeptidase Complex
Ubiquitin-Protein Ligases
Science
Article
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Humans
Mass spectrometry
Lysine
HEK 293 cells
Ubiquitination
General Chemistry
HCT116 Cells
HEK293 Cells
030104 developmental biology
Drug Resistance
Neoplasm
Ubiquitin ligases
Proteolysis
Ubiquitin-Conjugating Enzymes
Cancer cell
Biocatalysis
biology.protein
Myeloid Cell Leukemia Sequence 1 Protein
Suppressor
Carrier Proteins
Protein Processing
Post-Translational
Zdroj: Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021)
Nature Communications
ISSN: 2041-1723
Popis: 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.
The tumor suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF) and itself a target for ubiquitylation. Here, the authors show that TRIP12 mediates branched K11-linked ubiquitylation of FBW7, to regulate its stability and thus abundance of a subset of SCFFBW7 substrates.
Databáze: OpenAIRE
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