Negative Regulation of TLR Inflammatory Signaling by the SUMO-deconjugating Enzyme SENP6

The signaling of Toll-like receptors (TLRs) induces host defense against microbial invasion. Protein posttranslational modifications dynamically shape the strength and duration of the signaling pathways. It is intriguing to explore whether de-SUMOylation could modulate the TLR signaling. Here we identified SUMO-specific protease 6 (SENP6) as an intrinsic attenuator of the TLR-triggered inflammation. Depletion of SENP6 significantly potentiated the NF-κB-mediated induction of the proinflammatory genes. Consistently, SENP6-knockdown mice were more susceptible to endotoxin-induced sepsis. Mechanistically, the small ubiquitin-like modifier 2/3 (SUMO-2/3) is conjugated onto the Lysine residue 277 of NF-κB essential modifier (NEMO/IKKγ), and this impairs the deubiquitinase CYLD to bind NEMO, thus strengthening the inhibitor of κB kinase (IKK) activation. SENP6 reverses this process by catalyzing the de-SUMOylation of NEMO. Our study highlights the essential function of the SENP family in dampening TLR signaling and inflammation.Toll样受体（Toll-like receptors, TLRs）信号通路可诱导宿主产生对抗微生物入侵的防御反应。蛋白质翻译后修饰（protein posttranslational modifications）可动态调控信号通路的强度与持续时长。探究去SUMO化修饰能否调控TLR信号通路，是一项颇具研究价值的课题。本研究鉴定出SUMO特异性蛋白酶6（SUMO-specific protease 6, SENP6）作为TLR触发的炎症的内源性负调控因子。SENP6缺失可显著增强核因子κB（NF-κB）介导的促炎基因诱导表达。与之相符的是，SENP6敲低小鼠对内毒素诱导的脓毒症的易感性显著升高。从机制层面来看，小泛素样修饰蛋白2/3（small ubiquitin-like modifier 2/3, SUMO-2/3）可被偶联至核因子κB必需调节蛋白（NF-κB essential modifier, NEMO/IKKγ）的赖氨酸残基277位点，该修饰会削弱去泛素化酶CYLD与NEMO的结合能力，进而增强κB激酶抑制剂（inhibitor of κB kinase, IKK）的激活。SENP6可通过催化NEMO的去SUMO化修饰逆转这一过程。本研究阐明了SENP家族在抑制TLR信号通路与炎症反应中的核心功能。