title: CHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3.
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 TNFα). 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.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Jinho
authors.initials: J
authors.lastname: Seo
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Eun-Woo
authors.initials: EW
authors.lastname: Lee
authors.affiliation: Laboratory of Developmental Biology and Genetics, College of Veterinary Medicine, BK21Plus Program for Creative Veterinary Science Research, Interdisciplinary Program for Bioinformatics, BIO-MAX institute, Korea Mouse Phenotyping Center, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Hyerim
authors.identifier: http://orcid.org/0000-0003-3820-6699
authors.initials: H
authors.lastname: Sung
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Daehyeon
authors.initials: D
authors.lastname: Seong
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052 Zwijnaarde-Ghent, Belgium.|Inflammation Research Center, VIB, Technologiepark 927, 9052 Zwijnaarde-Ghent, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Dondelinger
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.|BRI, Korea Institute of Science and Technology, Seoul 136-791, Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Shin
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Manhyung
authors.initials: M
authors.lastname: Jeong
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Hae-Kyung
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Jung-Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Han
authors.affiliation: BRI, Korea Institute of Science and Technology, Seoul 136-791, Korea.
authors.forename: Cheolju
authors.initials: C
authors.lastname: Lee
authors.affiliation: Laboratory of Developmental Biology and Genetics, College of Veterinary Medicine, BK21Plus Program for Creative Veterinary Science Research, Interdisciplinary Program for Bioinformatics, BIO-MAX institute, Korea Mouse Phenotyping Center, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Je Kyung
authors.initials: JK
authors.lastname: Seong
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052 Zwijnaarde-Ghent, Belgium.|Inflammation Research Center, VIB, Technologiepark 927, 9052 Zwijnaarde-Ghent, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Jaewhan
authors.initials: J
authors.lastname: Song
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D018345:Mice, Knockout; D009336:Necrosis / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: C467728:STUB1 protein, human; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases