Ruan Hai-Hua, Zhang Zhen, Wang Su-Ying, Nickels Logan M, Tian Li, Qiao Jian-Jun, Zhu Jun
Tianjin Key Laboratory of Food Science and Biotechnology, College of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, China
Tianjin Key Laboratory of Food Science and Biotechnology, College of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, China.
Infect Immun. 2017 Jul 19;85(8). doi: 10.1128/IAI.00081-17. Print 2017 Aug.
serovar Typhimurium can inject effector proteins into host cells via type III secretion systems (T3SSs). These effector proteins modulate a variety of host transcriptional responses to facilitate bacterial growth and survival. Here we show that infection of host cells with Typhimurium specifically induces the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6). This TRAF6 ubiquitination is triggered by the pathogenicity island 1 (SPI-1) T3SS effectors SopB and SopE2. We also demonstrate that TRAF6 is involved in the SopB/SopE2-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3), a signaling event conducive to the intracellular growth of Typhimurium. Specifically, TRAF6 mediates lysine-63 ubiquitination within the Src homology 2 (SH2) domain of STAT3, which is an essential step for STAT3 membrane recruitment and subsequent phosphorylation in response to Typhimurium infection. TRAF6 ubiquitination participates in STAT3 phosphorylation rather than serving as only a hallmark of E3 ubiquitin ligase activation. Our results reveal a novel strategy in which Typhimurium T3SS effectors broaden their functions through the activation of host proteins in a ubiquitination-dependent manner to manipulate host cells into becoming a -friendly zone.
鼠伤寒血清型沙门氏菌可通过III型分泌系统（T3SSs）将效应蛋白注入宿主细胞。这些效应蛋白可调节多种宿主转录反应，以促进细菌的生长和存活。在此我们表明，用鼠伤寒沙门氏菌感染宿主细胞会特异性诱导肿瘤坏死因子受体相关因子6（TRAF6）的泛素化。这种TRAF6泛素化由毒力岛1（SPI-1）T3SS效应蛋白SopB和SopE2触发。我们还证明，TRAF6参与了SopB/SopE2诱导的信号转导和转录激活因子3（STAT3）的磷酸化，这一信号事件有利于鼠伤寒沙门氏菌在细胞内生长。具体而言，TRAF6介导STAT3的Src同源2（SH2）结构域内的赖氨酸63泛素化，这是STAT3膜募集以及随后对鼠伤寒沙门氏菌感染作出反应而发生磷酸化的关键步骤。TRAF6泛素化参与STAT3磷酸化，而不仅仅是作为E3泛素连接酶激活的标志。我们的结果揭示了一种新策略，即鼠伤寒沙门氏菌T3SS效应蛋白通过以泛素化依赖的方式激活宿主蛋白来拓宽其功能，从而将宿主细胞转变为一个“友好区域”。
