| First Author | Tu H | Year | 2021 |
| Journal | J Immunol | PubMed ID | 34162724 |
| Mgi Jnum | J:308019 | Mgi Id | MGI:6727808 |
| Doi | 10.4049/jimmunol.2100299 | Citation | Tu H, et al. (2021) Linear Ubiquitination of RIPK1 on Lys 612 Regulates Systemic Inflammation via Preventing Cell Death. J Immunol 207(2):602-612 |
| abstractText | Receptor-interacting protein kinase-1 (RIPK1) is a master regulator of the TNF-alpha-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-alpha-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 Ripk1(K612R/K612R) mice, which spontaneously develop systemic inflammation triggered by sustained emergency hematopoiesis. Mechanistically, without affecting NF-kappaB activation, Ripk1(K612R/K612R) mutation enhances apoptosis and necroptosis activation and promotes TNF-alpha-induced cell death. The systemic inflammation and hematopoietic disorders in Ripk1(K612R/K612R) mice are completely abolished by deleting TNF receptor 1 or both RIPK3 and Caspase-8. These data suggest the critical role of TNF-alpha-induced cell death in the resulting phenotype in Ripk1(K612R/K612R) mice. Together, our results demonstrate that linear ubiquitination of RIPK1 on K612 is essential for limiting TNF-alpha-induced cell death to further prevent systemic inflammation. |
