以前的研究工作從腸道致病性大腸桿菌識(shí)別出一組效應(yīng)物,，它們能抑制宿主“核因子-kB” (NF-kB) 信號作用，而它們當(dāng)中只有一個(gè),，即NleB,，是活體中細(xì)菌毒性所需的。本期Nature上發(fā)表的兩篇論文演示了NleB作用的獨(dú)特機(jī)制,。它直接以死亡受體信號復(fù)合物為作用目標(biāo),，結(jié)合到包括TNF受體、FAS,、RIPK1,、TRADD 和FADD在內(nèi)的多種含DD的蛋白的“死亡域”(DD) 上。DD被發(fā)現(xiàn)起一個(gè)N-acetylglucosamine (GlcNAc) 轉(zhuǎn)移酶的作用,，后者修飾一個(gè)保守的DD精氨酸,，阻斷“受體-適配體”相互作用。這些發(fā)現(xiàn)表明,，GlcNAc修飾是細(xì)菌毒性所必需的,，能夠調(diào)控死亡受體信號作用。（生物谷 Bioon.com）
生物谷推薦的英文摘要
Nature doi:10.1038/nature12436
Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains
Shan Li, Li Zhang, Qing Yao, Lin Li, Na Dong, Jie Rong, Wenqing Gao, Xiaojun Ding, Liming Sun, Xing Chen, She Chen & Feng Shao
The tumour necrosis factor (TNF) family is crucial for immune homeostasis, cell death and inflammation. These cytokines are recognized by members of the TNF receptor (TNFR) family of death receptors, including TNFR1 and TNFR2, and FAS and TNF-related apoptosis-inducing ligand (TRAIL) receptors1. Death receptor signalling requires death-domain-mediated homotypic/heterotypic interactions between the receptor and its downstream adaptors, including TNFR1-associated death domain protein (TRADD) and FAS-associated death domain protein (FADD)2. Here we discover that death domains in several proteins, including TRADD, FADD, RIPK1 and TNFR1, were directly inactivated by NleB, an enteropathogenic Escherichia coli (EPEC) type III secretion system effector known to inhibit host nuclear factor-κB (NF-κB) signalling3, 4. NleB contained an unprecedented N-acetylglucosamine (GlcNAc) transferase activity that specifically modified a conserved arginine in these death domains (Arg 235 in the TRADD death domain). NleB GlcNAcylation (the addition of GlcNAc onto a protein side chain) of death domains blocked homotypic/heterotypic death domain interactions and assembly of the oligomeric TNFR1 complex, thereby disrupting TNF signalling in EPEC-infected cells, including NF-κB signalling, apoptosis and necroptosis. Type-III-delivered NleB also blocked FAS ligand and TRAIL-induced cell death by preventing formation of a FADD-mediated death-inducing signalling complex (DISC). The arginine GlcNAc transferase activity of NleB was required for bacterial colonization in the mouse model of EPEC infection. The mechanism of action of NleB represents a new model by which bacteria counteract host defences, and also a previously unappreciated post-translational modification.
