期刊
NATURE CELL BIOLOGY
卷 18, 期 3, 页码 291-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3314
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资金
- National R&D Program for Cancer Control
- Ministry of Health & Welfare, Republic of Korea [NCC-1420300]
- National Research Foundation of Korea (NRF) - Ministry of Education [2012R1A6A3A04040105]
- Ministry of Science, ICT and Future Planning [NRF-2015R1A3A2066581]
- Flemish grants (Research Foundation Flanders) [FWO G.0875.11, FWO G.0973.11, FWO G.0A45.12N, FWO G.0787.13N, FWO G0E04.16N]
- Methusalem grant [BOF16/MET_V/007]
- Ghent University grants (MRP, GROUP-ID consortium)
- Foundation against Cancer [F94]
- VIB
- BK21 Plus project of the National Research Foundation of Korea Grant
- National Research Foundation of Korea (NRF)
- National Research Foundation of Korea [2012R1A6A3A04040105] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Receptor-interacting protein kinase 3 (RIPK3) functions as a key regulator of necroptosis. Here, we report that the RIPK3 expression level is negatively regulated by CHIP (carboxyl terminus of Hsp70-interacting protein; also known as STUB1) E3 ligase-mediated ubiquitylation. Chip(-/-) mouse embryonic fibroblasts and CHIP-depleted L929 and HT-29 cells exhibited higher levels of RIPK3 expression, resulting in increased sensitivity to necroptosis induced by TNF (also known as TNF alpha). These phenomena are due to the CHIP-mediated ubiquitylation of RIPK3, which leads to its lysosomal degradation. Interestingly, RIPK1 expression is also negatively regulated by CHIP-mediated ubiquitylation, validating the major role of CHIP in necrosome formation and sensitivity to TNF-mediated necroptosis. Chip(-/-) mice (C57BL/6) exhibit inflammation in the thymus and massive cell death and disintegration in the small intestinal tract, and die within a few weeks after birth. These phenotypes are rescued by crossing with Ripk3(-/-) mice. These results imply that CHIP is a bona fide negative regulator of the RIPK1-RIPK3 necrosome formation leading to desensitization of TNF-mediated necroptosis.
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