Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Nat Commun. 2022 Nov 22;13(1):7153. doi: 10.1038/s41467-022-34993-0.
Activation of RIPK1-driven cell death and inflammation play important roles in the progression of nonalcoholic steatohepatitis (NASH). However, the mechanism underlying RIPK1 activation in NASH remains unclear. Here we identified SENP1, a SUMO-specific protease, as a key endogenous inhibitor of RIPK1. SENP1 is progressively reduced in proportion to NASH severity in patients. Hepatocyte-specific SENP1-knockout mice develop spontaneous NASH-related phenotypes in a RIPK1 kinase-dependent manner. We demonstrate that SENP1 deficiency sensitizes cells to RIPK1 kinase-dependent apoptosis by promoting RIPK1 activation following TNFα stimulation. Mechanistically, SENP1 deSUMOylates RIPK1 in TNF-R1 signaling complex (TNF-RSC), keeping RIPK1 in check. Loss of SENP1 leads to SUMOylation of RIPK1, which re-orchestrates TNF-RSC and modulates the ubiquitination patterns and activity of RIPK1. Notably, genetic inhibition of RIPK1 effectively reverses disease progression in hepatocyte-specific SENP1-knockout male mice with high-fat-diet-induced nonalcoholic fatty liver. We propose that deSUMOylation of RIPK1 by SENP1 provides a pathophysiologically relevant cell death-restricting checkpoint that modulates RIPK1 activation in the pathogenesis of nonalcoholic steatohepatitis.
RIPK1 驱动的细胞死亡和炎症的激活在非酒精性脂肪性肝炎（NASH）的进展中起着重要作用。然而，NASH 中 RIPK1 激活的机制尚不清楚。在这里，我们鉴定了 SENP1，一种 SUMO 特异性蛋白酶，作为 RIPK1 的关键内源性抑制剂。SENP1 的比例随着患者 NASH 严重程度的增加而逐渐降低。肝细胞特异性 SENP1 敲除小鼠以 RIPK1 激酶依赖性方式自发发展出与 NASH 相关的表型。我们证明，SENP1 缺乏通过促进 TNFα 刺激后的 RIPK1 激活，使细胞对 RIPK1 激酶依赖性凋亡敏感。在机制上，SENP1 在 TNF-R1 信号转导复合物（TNF-RSC）中去 SUMO 化 RIPK1，从而抑制 RIPK1。SENP1 的缺失导致 RIPK1 的 SUMO 化，这重新调整了 TNF-RSC，并调节了 RIPK1 的泛素化模式和活性。值得注意的是，RIPK1 的遗传抑制可有效逆转高脂肪饮食诱导的非酒精性脂肪肝中肝细胞特异性 SENP1 敲除雄性小鼠的疾病进展。我们提出，SENP1 对 RIPK1 的去 SUMO 化提供了一个与生理相关的细胞死亡限制检查点，调节了 RIPK1 在非酒精性脂肪性肝炎发病机制中的激活。
