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. © 2013 liu et al.