CHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3

Title
CHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3
Authors
이철주서진호이은우성혜림성대현Yves Dondelinger신지혜정만형이혜경김정훈한수연성재경Peter Vandenabeele송재환
Issue Date
2016-02
Publisher
Nature cell biology
Citation
VOL 18, NO 3-304
Abstract
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
URI
http://pubs.kist.re.kr/handle/201004/65036
ISSN
1465-7392
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