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

Jinho Seo, Eun Woo Lee, Hyerim Sung, Daehyeon Seong, Yves Dondelinger, Jihye Shin, Manhyung Jeong, Hae Kyung Lee, Jung Hoon Kim, Su Yeon Han, Cheolju Lee, Je Kyung Seong, Peter Vandenabeele, Jaewhan Song

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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). 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.

Original languageEnglish
Pages (from-to)291-302
Number of pages12
JournalNature Cell Biology
Volume18
Issue number3
DOIs
Publication statusPublished - 2016 Feb 25

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All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Seo, J., Lee, E. W., Sung, H., Seong, D., Dondelinger, Y., Shin, J., Jeong, M., Lee, H. K., Kim, J. H., Han, S. Y., Lee, C., Seong, J. K., Vandenabeele, P., & Song, J. (2016). CHIP controls necroptosis through ubiquitylation-and lysosome-dependent degradation of RIPK3. Nature Cell Biology, 18(3), 291-302. https://doi.org/10.1038/ncb3314