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 language | English |
|---|---|
| Pages (from-to) | 291-302 |
| Number of pages | 12 |
| Journal | Nature Cell Biology |
| Volume | 18 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2016 Feb 25 |
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All Science Journal Classification (ASJC) codes
- Cell Biology
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CHIP controls necroptosis through ubiquitylation-and lysosome-dependent degradation of RIPK3. / 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.
In: Nature Cell Biology, Vol. 18, No. 3, 25.02.2016, p. 291-302.Research output: Contribution to journal › Article
TY - JOUR
T1 - CHIP controls necroptosis through ubiquitylation-and lysosome-dependent degradation of RIPK3
AU - Seo, Jinho
AU - Lee, Eun Woo
AU - Sung, Hyerim
AU - Seong, Daehyeon
AU - Dondelinger, Yves
AU - Shin, Jihye
AU - Jeong, Manhyung
AU - Lee, Hae Kyung
AU - Kim, Jung Hoon
AU - Han, Su Yeon
AU - Lee, Cheolju
AU - Seong, Je Kyung
AU - Vandenabeele, Peter
AU - Song, Jaewhan
PY - 2016/2/25
Y1 - 2016/2/25
N2 - 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.
AB - 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.
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U2 - 10.1038/ncb3314
DO - 10.1038/ncb3314
M3 - Article
VL - 18
SP - 291
EP - 302
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 3
ER -