Seo, Jinho Lee, Eun-Woo Sung, Hyerim Seong, Daehyeon Dondelinger, Yves Shin, Jihye Jeong, Manhyung Lee, Hae-Kyung Kim, Jung-Hoon Han, Su Yeon Lee, Cheolju Seong, Je Kyung Vandenabeele, Peter Song, Jaewhan 2024-01-20T05:00:23Z 2024-01-20T05:00:23Z 2021-09-04 2016-03 1465-7392 https://pubs.kist.re.kr/handle/201004/124348 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. English NATURE PUBLISHING GROUP MIXED LINEAGE KINASE DOMAIN-LIKE PROTEIN CELL-DEATH PROGRAMMED NECROSIS APOPTOSIS MLKL UBIQUITINATION CASPASE-8 ROLES FADD CHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3 Article 10.1038/ncb3314 1 NATURE CELL BIOLOGY, v.18, no.3, pp.291 - + NATURE CELL BIOLOGY 18 3 291 + scie scopus 000371031300010 2-s2.0-84959241995 Cell Biology Cell Biology Article MIXED LINEAGE KINASE DOMAIN-LIKE PROTEIN CELL-DEATH PROGRAMMED NECROSIS APOPTOSIS MLKL UBIQUITINATION CASPASE-8 ROLES FADD