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

PLoS Pathogens

Xing Liu¹  Wei Chen¹  Chen Wang¹  Qiang Wang¹  Li Li¹ 

[1] State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

关键词: Immunoprecipitation;    Small interfering RNAs;    SUMOylation;    Transcription factors;    Toll-like receptor signaling;    Immune receptor signaling;    Transfection;    Immunoblot analysis;   

DOI  :  10.1371/journal.ppat.1003480

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY