Nature：东京大学研究揭示痢疾杆菌攻击人体机制

 S. flexneri OspI 蛋白晶体结构

东京大学教授Chihiro Sasakawa领导的研究小组日前发现了痢疾杆菌（ Shigella flexneri ）借助特殊蛋白质破坏人体免疫功能的机制。这一发现有望促进开发新的治疗药物。相关论文3月11号在线发表于《Nature》。

研究小组发现，痢疾杆菌侵入肠道下部的上皮细胞时，人体会激活免疫功能，力图击退痢疾杆菌。但痢疾杆菌却抢先一步，提前分泌一种名为“OspI”的蛋白质，然后吸附到激活免疫功能的人体“UBC13”蛋白质上，导致人体无法充分免疫。

研究人员成功使“OspI”蛋白质结晶化，然后用大型同步辐射光源“SPring－8”分析其结构，并根据该蛋白质的立体结构，确认其各种特点。

Chihiro Sasakawa指出，如能在此次研究基础上开发出以痢疾杆菌分泌的“OspI”蛋白质为靶向的药物，就有望保护人体免疫功能，消灭痢疾杆菌。今后，研究小组准备继续寻找能攻击“OspI”蛋白质的物质。（生物谷 bioon.com）

doi:10.1038/nature10894
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The Shigella flexneri effector OspI deamidates UBC13 to dampen the inflammatory response

Takahito Sanada,Minsoo Kim,Hitomi Mimuro,Masato Suzuki,Michinaga Ogawa,Akiho Oyama,Hiroshi Ashida,Taira Kobayashi,Tomohiro Koyama,Shinya Nagai,Yuri Shibata,Jin Gohda,Jun-ichiro Inoue,Tsunehiro Mizushima，Chihiro Sasakawa

Many bacterial pathogens can enter various host cells and then survive intracellularly, transiently evade humoral immunity, and further disseminate to other cells and tissues. When bacteria enter host cells and replicate intracellularly, the host cells sense the invading bacteria as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) by way of various pattern recognition receptors. As a result, the host cells induce alarm signals that activate the innate immune system1. Therefore, bacteria must modulate host inflammatory signalling and dampen these alarm signals2, 3, 4. How pathogens do this after invading epithelial cells remains unclear, however. Here we show that OspI, a Shigella flexneri effector encoded by ORF169b on the large plasmid and delivered by the type ΙΙΙ secretion system, dampens acute inflammatory responses during bacterial invasion by suppressing the tumour-necrosis factor (TNF)-receptor-associated factor 6 (TRAF6)-mediated signalling pathway. OspI is a glutamine deamidase that selectively deamidates the glutamine residue at position 100 in UBC13 to a glutamic acid residue. Consequently, the E2 ubiquitin-conjugating activity required for TRAF6 activation is inhibited, allowing S. flexneri OspI to modulate the diacylglycerol–CBM (CARD–BCL10–MALT1) complex–TRAF6–nuclear-factor-κB signalling pathway. We determined the 2.0 ? crystal structure of OspI, which contains a putative cysteine–histidine–aspartic acid catalytic triad. A mutational analysis showed this catalytic triad to be essential for the deamidation of UBC13. Our results suggest that S. flexneri inhibits acute inflammatory responses in the initial stage of infection by targeting the UBC13–TRAF6 complex.