Page 10 - G. Cell differentiation. division. and death

[G. Cell differentiation, division, and death-8]

CHIP negatively regulates necroptosis via ubiquitylation-

meidated lysosomal degradation of RIPK1 and RIPK3

Choong-Sil Lee¹˙²˙#, Jinho Seo³˙#, Eun-Woo Lee⁴˙#, Jaewhan Song¹˙²˙*

¹Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea,

²Interdisciplinary Program of Integrated OMICS for Biomedical Science, WCU, Yonsei University, Seoul Korea,
Korea, ³Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB),

Daejeon 34141, Korea, ⁴Metabolic Regulation Research Center, Korea Research Institute of Bioscience and
Biotechnology (KRIBB), Daejeon 34141, Korea

Receptor-interacting protein kinase 3 (RIPK3) is a key protein involved in necroptosis. Here, we report that CHIP
(carboxyl terminus of Hsp70-interacting protein, STUB1) negatively regulates RIPK3 protein levels by E3 ligase
activity-mediated ubiquitylation. Chip knockout (KO) mouse embryonic fibroblasts and CHIP-depleted L929 and HT-

29 cells exhibited higher levels of RIPK3 protein, resulting in increased TNFα-induced necroptosis. CHIP-mediated
ubiquitylation of RIPK3 leads to its lysosomal degradation. RIPK1, another key protein associated with necroptosis,

is also negatively regulated by CHIP-mediated ubiquitylation. Chip and Ripk3 double knockout (DKO) rescued
phenotypes of Chip KO mice such as inflammation in the thymus, massive cell death and disintegration of the small

intestinal tract and, death within a few weeks after birth. These results suggest that CHIP is a negative regulator of
the RIPK1-RIPK3 necrosome complex, thereby suppressing TNFα-induced necroptosis.