Publication Date:
2012-03-13
Description:
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 system. Therefore, bacteria must modulate host inflammatory signalling and dampen these alarm signals. 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 IotaIotaIota 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-kappaB signalling pathway. We determined the 2.0 A 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sanada, Takahito -- Kim, Minsoo -- Mimuro, Hitomi -- Suzuki, Masato -- Ogawa, Michinaga -- Oyama, Akiho -- Ashida, Hiroshi -- Kobayashi, Taira -- Koyama, Tomohiro -- Nagai, Shinya -- Shibata, Yuri -- Gohda, Jin -- Inoue, Jun-ichiro -- Mizushima, Tsunehiro -- Sasakawa, Chihiro -- England -- Nature. 2012 Mar 11;483(7391):623-6. doi: 10.1038/nature10894.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Infectious Disease Control, International Research Center for Infectious Diseases, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22407319" target="_blank"〉PubMed〈/a〉
Keywords:
*Adaptor Proteins, Signal Transducing/metabolism
;
Amidohydrolases/*chemistry/genetics/*metabolism
;
Amino Acid Sequence
;
Animals
;
Aspartic Acid/metabolism
;
Biocatalysis
;
Caspases/metabolism
;
Catalytic Domain/genetics
;
Crystallography, X-Ray
;
Cysteine/metabolism
;
DNA Mutational Analysis
;
Diglycerides/antagonists & inhibitors/metabolism
;
Dysentery, Bacillary/microbiology
;
Glutamic Acid/metabolism
;
Glutamine/metabolism
;
HEK293 Cells
;
HeLa Cells
;
Histidine/metabolism
;
Humans
;
Immunity, Innate
;
Inflammation/enzymology/*immunology/*metabolism
;
Mice
;
Models, Molecular
;
Molecular Sequence Data
;
NF-kappa B/metabolism
;
Neoplasm Proteins/metabolism
;
Shigella flexneri/*enzymology/genetics/*immunology/pathogenicity
;
TNF Receptor-Associated Factor 6/deficiency/genetics/metabolism
;
Ubiquitin-Conjugating Enzymes/chemistry/genetics/*metabolism
;
Virulence Factors/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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