Linear Ubiquitination of RIPK1 on Lys612 Regulates Systemic Inflammation via Preventing Cell Death
| Autor: | Jie Zhang, Xin Lin, Hailin Tu, Yong Tang, Donghyun Joo, Liqing Cheng, Xueqiang Zhao |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 207:602-612 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.2100299 |
| Popis: | Receptor-interacting protein kinase-1 (RIPK1) is a master regulator of the TNF-α–induced cell death program. The function of RIPK1 is tightly controlled by posttranslational modifications, including linear ubiquitin chain assembly complex–mediated linear ubiquitination. However, the physiological function and molecular mechanism by which linear ubiquitination of RIPK1 regulates TNF-α–induced intracellular signaling remain unclear. In this article, we identified Lys627 residue as a major linear ubiquitination site in human RIPK1 (or Lys612 in murine RIPK1) and generated Ripk1K612R/K612R mice, which spontaneously develop systemic inflammation triggered by sustained emergency hematopoiesis. Mechanistically, without affecting NF-κB activation, Ripk1K612R/K612R mutation enhances apoptosis and necroptosis activation and promotes TNF-α–induced cell death. The systemic inflammation and hematopoietic disorders in Ripk1K612R/K612R mice are completely abolished by deleting TNF receptor 1 or both RIPK3 and Caspase-8. These data suggest the critical role of TNF-α–induced cell death in the resulting phenotype in Ripk1K612R/K612R mice. Together, our results demonstrate that linear ubiquitination of RIPK1 on K612 is essential for limiting TNF-α–induced cell death to further prevent systemic inflammation. |
| Databáze: | OpenAIRE |
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