LeBlanc Philippe M, Yeretssian Garabet, Rutherford Nancy, Doiron Karine, Nadiri Amal, Zhu Lei, Green Douglas R, Gruenheid Samantha, Saleh Maya
Department of Medicine, Division of Critical Care, and Centre for Study of Host Resistance, McGill University, Montreal H3A 1A1, Canada.
Cell Host Microbe. 2008 Mar 13;3(3):146-57. doi: 10.1016/j.chom.2008.02.004.
Bacterial sensing by intracellular Nod proteins and other Nod-like receptors (NLRs) activates signaling pathways that mediate inflammation and pathogen clearance. Nod1 and Nod2 associate with the kinase Rip2 to stimulate NF-kappaB signaling. Other cytosolic NLRs assemble caspase-1-activating multiprotein complexes termed inflammasomes. Caspase-12 modulates the caspase-1 inflammasome, but unlike other NLRs, Nod1 and Nod2 have not been linked to caspases, and mechanisms regulating the Nod-Rip2 complex are less clear. We report that caspase-12 dampens mucosal immunity to bacterial infection independent of its effects on caspase-1. Caspase-12 deficiency enhances production of antimicrobial peptides, cytokines, and chemokines to entric pathogens, an effect dependent on bacterial type III secretion and the Nod pathway. Mechanistically, caspase-12 binds to Rip2, displacing Traf6 from the signaling complex, inhibiting its ubiquitin ligase activity, and blunting NF-kappaB activation. Nod activation and resulting antimicrobial peptide production constitute an early innate defense mechanism, and caspase-12 inhibits this mucosal antimicrobial response.
细胞内Nod蛋白和其他Nod样受体（NLR）对细菌的感知会激活介导炎症和病原体清除的信号通路。Nod1和Nod2与激酶Rip2结合以刺激NF-κB信号传导。其他胞质NLR组装称为炎性小体的激活半胱天冬酶-1的多蛋白复合物。半胱天冬酶-12调节半胱天冬酶-1炎性小体，但与其他NLR不同，Nod1和Nod2尚未与半胱天冬酶联系起来，调节Nod-Rip2复合物的机制尚不清楚。我们报告称，半胱天冬酶-12会削弱对细菌感染的黏膜免疫，且与其对半胱天冬酶-1的影响无关。半胱天冬酶-12缺陷会增强对肠道病原体的抗菌肽、细胞因子和趋化因子的产生，这种效应依赖于细菌III型分泌和Nod途径。从机制上讲，半胱天冬酶-12与Rip2结合，将Traf6从信号复合物中置换出来，抑制其泛素连接酶活性，并减弱NF-κB激活。Nod激活及由此产生的抗菌肽产生构成了一种早期固有防御机制，而半胱天冬酶-12会抑制这种黏膜抗菌反应。
