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Updated: Jan 24, 2026
In Vitro Analysis of E3 Ubiquitin Ligase Function
Published on: May 14, 2021
Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation
Jieqiong Zhang1, Joshua D Webster2, Debra L Dugger1
1Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA.
Abstract:
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.
Insights
Cellular inhibitor of apoptosis proteins cIAP1 and cIAP2 are crucial for maintaining homeostasis by suppressing cell death pathways. Their deficiency leads to inflammation and death, highlighting their role in preventing aberrant apoptosis.
Area of Science:
- Cellular and Molecular Biology
- Immunology
- Physiology
Background:
- Cellular inhibitor of apoptosis proteins (cIAP1/2) regulate NF-κB signaling and cell survival through protein ubiquitination.
- The specific in vivo functions of cIAP1/2 in maintaining tissue homeostasis and preventing cell death remain incompletely understood.
Purpose of the Study:
- To elucidate the role of cIAP1/2 in vivo by examining the consequences of cIAP2 deletion in adult cIAP1-deficient mice.
- To investigate the mechanisms underlying aberrant cell death and inflammation observed in cIAP1/2-deficient models.
Main Methods:
- Generation of adult cIAP1-deficient mice with subsequent cIAP2 elimination.
- Analysis of inflammatory markers, cell death pathways (caspase-3, caspase-8, RIPK1, RIPK3, MLKL), and survival rates.
- Pharmacological inhibition of NF-κB-inducing kinase (NIK).
Main Results:
- cIAP1/2 deficiency rapidly induces severe weight loss, inflammation, and aberrant cell death in the liver and intestine, evidenced by cleaved caspases-3 and -8.
- Simultaneous deletion of Caspase-8 (Casp8) and Receptor-Interacting Protein Kinase 3 (Ripk3) rescues aberrant cell death, reduces inflammation, and prolongs survival.
- Inhibition of NIK alleviates residual inflammation in mice lacking cIAP1/2, Casp8, and Ripk3.
- Loss of Casp8 and Mixed Lineage Kinase Domain-Like protein (MLKL) prevents embryonic lethality in cIAP1/2-deficient mice, while MLKL loss alone does not.
Conclusions:
- A primary function of cIAP1/2 in vivo is the suppression of caspase-8-dependent cell death.
- cIAP1/2 play a critical role in preventing RIPK1/RIPK3/caspase-8-mediated necroptosis and apoptosis, thereby maintaining tissue integrity and organismal survival.
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