東京大學(xué)教授Chihiro Sasakawa領(lǐng)導(dǎo)的研究小組日前發(fā)現(xiàn)了痢疾桿菌（ Shigella flexneri ）借助特殊蛋白質(zhì)破壞人體免疫功能的機(jī)制,。這一發(fā)現(xiàn)有望促進(jìn)開發(fā)新的治療藥物,。相關(guān)論文3月11號在線發(fā)表于《Nature》。
研究小組發(fā)現(xiàn),，痢疾桿菌侵入腸道下部的上皮細(xì)胞時,，人體會激活免疫功能,，力圖擊退痢疾桿菌,。但痢疾桿菌卻搶先一步，提前分泌一種名為“OspI”的蛋白質(zhì),，然后吸附到激活免疫功能的人體“UBC13”蛋白質(zhì)上,，導(dǎo)致人體無法充分免疫。
研究人員成功使“OspI”蛋白質(zhì)結(jié)晶化,，然后用大型同步輻射光源“SPring－8”分析其結(jié)構(gòu),，并根據(jù)該蛋白質(zhì)的立體結(jié)構(gòu)，確認(rèn)其各種特點(diǎn),。
Chihiro Sasakawa指出,，如能在此次研究基礎(chǔ)上開發(fā)出以痢疾桿菌分泌的“OspI”蛋白質(zhì)為靶向的藥物，就有望保護(hù)人體免疫功能,，消滅痢疾桿菌,。今后，研究小組準(zhǔn)備繼續(xù)尋找能攻擊“OspI”蛋白質(zhì)的物質(zhì),。（生物谷 bioon.com）
doi:10.1038/nature10894
PMC:
PMID:
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.
