Proteolytic elimination of N-myristoyl modifications by the Shigella virulence factor IpaJ.
Proteolytic elimination of N-myristoyl modifications by the Shigella virulence factor IpaJ.
复制标题
作者：
蛋白质N-豆蔻酰化是一种14碳脂肪酸修饰，在真核生物中是保守的，发生在近1%的细胞蛋白质组上。肉豆蔻酰基促进动态蛋白质-蛋白质和蛋白质-膜相互作用（称为肉豆蔻酰基开关）的能力使其成为许多信号转导系统的基本特征。因此，促进蛋白质去豆蔻酰化的致病策略将显著改变受感染宿主细胞的信号转导景观。在这里，我们描述了一个不可逆的机制，蛋白脱豆蔻酰化催化的入侵质粒抗原J（IpaJ），以前未知的福氏志贺菌III型效应蛋白与半胱氨酸蛋白酶活性。酵母遗传筛选IpaJ底物确定ADP-核糖基化因子（ARF）1 p和ARF 2 p，小分子量GTP酶，调节货物运输通过高尔基体。质谱分析表明，IpaJ切割N-肉豆蔻酰甘氨酸-2和天冬酰胺-3之间的人ARF 1的肽键，从而提供了一种新的机制，宿主分泌抑制细菌病原体。我们进一步证明，IpaJ切割一系列参与细胞生长，信号转导，自噬体成熟和细胞器功能的N-豆蔻酰化蛋白。总之，这些发现表明了一个以前未被认识到的致病机制，为位点特异性消除N-肉豆蔻酰蛋白修饰。
Protein N-myristoylation is a 14-carbon fatty-acid modification that is conserved across eukaryotic species and occurs on nearly 1% of the cellular proteome. The ability of the myristoyl group to facilitate dynamic protein–protein and protein–membrane interactions (known as the myristoyl switch) makes it an essential feature of many signal transduction systems. Thus pathogenic strategies that facilitate protein demyristoylation would markedly alter the signalling landscape of infected host cells. Here we describe an irreversible mechanism of protein demyristoylation catalysed by invasion plasmid antigen J (IpaJ), a previously uncharacterized Shigella flexneri type III effector protein with cysteine protease activity. A yeast genetic screen for IpaJ substrates identified ADP-ribosylation factor (ARF)1p and ARF2p, small molecular mass GTPases that regulate cargo transport through the Golgi apparatus. Mass spectrometry showed that IpaJ cleaved the peptide bond between N-myristoylated glycine-2 and asparagine-3 of human ARF1, thereby providing a new mechanism for host secretory inhibition by a bacterial pathogen. We further demonstrate that IpaJ cleaves an array of N-myristoylated proteins involved in cellular growth, signal transduction, autophagasome maturation and organelle function. Taken together, these findings show a previously unrecognized pathogenic mechanism for the site-specific elimination of N-myristoyl protein modification.
登录
查看更多内容
DOI：
10.1126/science.1227026
发表时间：
2012-11-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Choy A;Dancourt J;Mugo B;O'Connor TJ;Isberg RR;Melia TJ;Roy CR
通讯作者：
Roy CR
影响因子：
56.9
作者：
Rivera, VM;Wang, XR;Clackson, T
通讯作者：
Clackson, T
影响因子：
64.5
作者：
Dong, Na;Zhu, Yongqun;Shao, Feng
通讯作者：
Shao, Feng
DOI：
10.1016/j.str.2008.10.020
发表时间：
2009-01-14
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Liu Y;Kahn RA;Prestegard JH
通讯作者：
Prestegard JH
一种功能性基因组酵母筛选，以鉴定致病性细菌蛋白。
影响因子：
6.7
作者：
Slagowski, Naomi L.;Kramer, Roger W.;Morrison, Monica F.;LaBaer, Joshua;Lesser, Cammie F.
通讯作者：
Lesser, Cammie F.