SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation

The mechanism underlying RIPK1-driven cell death and inflammation, a key process in the progression of nonalcoholic steatohepatitis, 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 TNFalpha 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. Liver mRNA profiles of E14.5d Senp1+/+ ,Senp1-/-, Senp1-/-;RIPK1D138N/D138N mice and 4-month old Senp1flox/flox, Senp1flox/flox;AlbCre/+ mice受体相互作用蛋白激酶1（RIPK1）介导的细胞死亡与炎症是非酒精性脂肪性肝炎（nonalcoholic steatohepatitis, NASH）进展中的关键过程，但其潜在机制仍未阐明。本研究鉴定出SUMO特异性蛋白酶（SUMO-specific protease）SENP1为RIPK1的关键内源性抑制剂。患者体内SENP1的表达水平随NASH病情严重程度呈进行性降低。肝细胞特异性敲除SENP1的小鼠可通过RIPK1激酶依赖性方式自发出现NASH相关表型。研究证实，SENP1缺失可通过促进肿瘤坏死因子α（TNFα）刺激下的RIPK1活化，使细胞对RIPK1激酶依赖性凋亡更为敏感。机制层面，SENP1可在肿瘤坏死因子受体1信号复合物（TNF-R1 signaling complex, TNF-RSC）中对RIPK1进行去SUMO化修饰，从而抑制RIPK1的活性。SENP1缺失会导致RIPK1发生SUMO化修饰，进而重新调控TNF-RSC的组装，并改变RIPK1的泛素化模式与活性。值得注意的是，对RIPK1进行遗传学抑制可有效逆转高脂饮食诱导非酒精性脂肪性肝病的肝细胞特异性SENP1敲除雄性小鼠的疾病进程。本研究提出，SENP1对RIPK1的去SUMO化修饰可提供一个与病理生理学相关的细胞死亡限制性检查点，在非酒精性脂肪性肝炎的发病机制中调控RIPK1的活化。本数据集涵盖E14.5天的Senp1+/+、Senp1-/-、Senp1-/-;RIPK1D138N/D138N小鼠，以及4月龄的Senp1flox/flox、Senp1flox/flox;AlbCre/+小鼠的肝脏mRNA表达谱。