Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation
Summary: Cellular inhibitor of apoptosis proteins cIAP1 and cIAP2 ubiquitinate nuclear factor κB (NF-κB)-inducing kinase (NIK) to suppress non-canonical NF-κB signaling and substrates such as receptor interacting protein kinase 1 (RIPK1) to promote cell survival. We investigate how these functions c...
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doaj-8a63ee8ba40f4915a2963d7757c79bef2020-11-25T00:46:47ZengElsevierCell Reports2211-12472019-05-0127926792689.e3Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent InflammationJieqiong Zhang0Joshua D. Webster1Debra L. Dugger2Tatiana Goncharov3Merone Roose-Girma4Jeffrey Hung5Youngsu C. Kwon6Domagoj Vucic7Kim Newton8Vishva M. Dixit9Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USADepartment of Pathology, Genentech, South San Francisco, CA 94080, USADepartment of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USADepartment of Early Discovery Biochemistry, Genentech, South San Francisco, CA 94080, USADepartment of Molecular Biology, Genentech, South San Francisco, CA 94080, USADepartment of Pathology, Genentech, South San Francisco, CA 94080, USADepartment of Translational Immunology, Genentech, South San Francisco, CA 94080, USADepartment of Early Discovery Biochemistry, Genentech, South San Francisco, CA 94080, USADepartment of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA; Corresponding authorDepartment of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA; Corresponding authorSummary: Cellular inhibitor of apoptosis proteins cIAP1 and cIAP2 ubiquitinate nuclear factor κB (NF-κB)-inducing kinase (NIK) to suppress non-canonical NF-κB signaling and substrates such as receptor interacting protein kinase 1 (RIPK1) to promote cell survival. We investigate how these functions contribute to homeostasis by eliminating cIap2 from adult cIap1-deficient mice. cIAP1 and cIAP2 (cIAP1/2) deficiency causes rapid weight loss and inflammation, with aberrant cell death, indicated by cleaved caspases-3 and -8, prevalent in intestine and liver. Deletion of Casp8 and Ripk3 prevents this aberrant cell death, reduces the inflammation, and prolongs mouse survival, whereas Ripk3 loss alone offers little benefit. Residual inflammation in mice lacking cIap1/2, Casp8, and Ripk3 is reduced by inhibition of NIK. Loss of Casp8 and Mlkl (mixed lineage kinase domain-like), but not Mlkl loss alone, also prevents cIAP1/2-deficient mice from dying around embryonic day 11. Therefore, a major function of cIAP1/2 in vivo is to suppress caspase-8-dependent cell death. : Zhang et al. use mouse genetics to show that the ubiquitin ligases cIAP1 and cIAP2 are critical for suppressing pro-inflammatory caspase-8-dependent cell death. Loss of caspase-8 (in combination with RIPK3 or MLKL loss) prevents embryonic lethality due to cIAP1/2 deficiency and ameliorates inflammation when cIAP1/2 are deleted from adult mice. Keywords: cIAP1, cIAP2, apoptosis, caspase-8, NIKhttp://www.sciencedirect.com/science/article/pii/S2211124719306011 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jieqiong Zhang Joshua D. Webster Debra L. Dugger Tatiana Goncharov Merone Roose-Girma Jeffrey Hung Youngsu C. Kwon Domagoj Vucic Kim Newton Vishva M. Dixit |
spellingShingle |
Jieqiong Zhang Joshua D. Webster Debra L. Dugger Tatiana Goncharov Merone Roose-Girma Jeffrey Hung Youngsu C. Kwon Domagoj Vucic Kim Newton Vishva M. Dixit Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation Cell Reports |
author_facet |
Jieqiong Zhang Joshua D. Webster Debra L. Dugger Tatiana Goncharov Merone Roose-Girma Jeffrey Hung Youngsu C. Kwon Domagoj Vucic Kim Newton Vishva M. Dixit |
author_sort |
Jieqiong Zhang |
title |
Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation |
title_short |
Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation |
title_full |
Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation |
title_fullStr |
Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation |
title_full_unstemmed |
Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation |
title_sort |
ubiquitin ligases ciap1 and ciap2 limit cell death to prevent inflammation |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2019-05-01 |
description |
Summary: Cellular inhibitor of apoptosis proteins cIAP1 and cIAP2 ubiquitinate nuclear factor κB (NF-κB)-inducing kinase (NIK) to suppress non-canonical NF-κB signaling and substrates such as receptor interacting protein kinase 1 (RIPK1) to promote cell survival. We investigate how these functions contribute to homeostasis by eliminating cIap2 from adult cIap1-deficient mice. cIAP1 and cIAP2 (cIAP1/2) deficiency causes rapid weight loss and inflammation, with aberrant cell death, indicated by cleaved caspases-3 and -8, prevalent in intestine and liver. Deletion of Casp8 and Ripk3 prevents this aberrant cell death, reduces the inflammation, and prolongs mouse survival, whereas Ripk3 loss alone offers little benefit. Residual inflammation in mice lacking cIap1/2, Casp8, and Ripk3 is reduced by inhibition of NIK. Loss of Casp8 and Mlkl (mixed lineage kinase domain-like), but not Mlkl loss alone, also prevents cIAP1/2-deficient mice from dying around embryonic day 11. Therefore, a major function of cIAP1/2 in vivo is to suppress caspase-8-dependent cell death. : Zhang et al. use mouse genetics to show that the ubiquitin ligases cIAP1 and cIAP2 are critical for suppressing pro-inflammatory caspase-8-dependent cell death. Loss of caspase-8 (in combination with RIPK3 or MLKL loss) prevents embryonic lethality due to cIAP1/2 deficiency and ameliorates inflammation when cIAP1/2 are deleted from adult mice. Keywords: cIAP1, cIAP2, apoptosis, caspase-8, NIK |
url |
http://www.sciencedirect.com/science/article/pii/S2211124719306011 |
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