A unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5
| Autor: | Wenke Shi, Kai Huang, Jing Song, Wei Han, Jiahuai Han, Chenchen Ruan, Jun Liu, Tao Han, Su-Qin Wu, Yingying Zhang, Lang Li, Ye-hsuan Sun, Yuxia Zhang |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Physiology
Mutant Apoptosis medicine.disease_cause Biochemistry Mice Cell Signaling Immune Physiology Medicine and Health Sciences Biology (General) Immune Response Apoptotic Signaling Cascade Caspase 8 Innate Immune System Mutation Cell Death Protein Kinase Signaling Cascade Kinase General Neuroscience Signaling Cascades Cell biology Receptors Tumor Necrosis Factor Type I Cell Processes Caspases Receptor-Interacting Protein Serine-Threonine Kinases embryonic structures Cytokines General Agricultural and Biological Sciences Signal Transduction QH301-705.5 Necroptosis Primary Cell Culture Immunology Embryonic Development Biology General Biochemistry Genetics and Molecular Biology Necrotic Cell Death RIPK1 Signs and Symptoms Protein Domains medicine Animals Inflammation General Immunology and Microbiology Embryogenesis Biology and Life Sciences Proteins Cell Biology Molecular Development Embryonic stem cell Primer Immune System Clinical Medicine Developmental Biology |
| Zdroj: | PLoS Biology, Vol 19, Iss 8, p e3001304 (2021) PLoS Biology |
| ISSN: | 1545-7885 |
| DOI: | 10.1371/journal.pbio.3001304 |
| Popis: | Tumor necrosis factor receptor-1 (TNFR1) signaling, apart from its pleiotropic functions in inflammation, plays a role in embryogenesis as deficiency of varieties of its downstream molecules leads to embryonic lethality in mice. Caspase-8 noncleavable receptor interacting serine/threonine kinase 1 (RIPK1) mutations occur naturally in humans, and the corresponding D325A mutation in murine RIPK1 leads to death at early midgestation. It is known that both the demise ofRipk1D325A/D325Aembryos and the death ofCasp8−/−mice are initiated by TNFR1, but they are mediated by apoptosis and necroptosis, respectively. Here, we show that the defects inRipk1D325A/D325Aembryos occur at embryonic day 10.5 (E10.5), earlier than that caused byCasp8knockout. By analyzing a series of genetically mutated mice, we elucidated a mechanism that leads to the lethality ofRipk1D325A/D325Aembryos and compared it with that underliesCasp8deletion-mediated lethality. We revealed that the apoptosis inRipk1D325A/D325Aembryos requires a scaffold function of RIPK3 and enzymatically active caspase-8. Unexpectedly, caspase-1 and caspase-11 are downstream of activated caspase-8, and concurrent depletion ofCasp1andCasp11postpones the E10.5 lethality to embryonic day 13.5 (E13.5). Moreover, caspase-3 is an executioner of apoptosis at E10.5 inRipk1D325A/D325Amice as its deletion extends life ofRipk1D325A/D325Amice to embryonic day 11.5 (E11.5). Hence, an unexpected death pathway of TNFR1 controls RIPK1 D325A mutation-induced lethality at E10.5. |
| Databáze: | OpenAIRE |
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