Journal
NATURE
Volume 483, Issue 7391, Pages 623-U149Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature10894
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Categories
Funding
- Japan Initiative for Global Research Network on Infectious Diseases
- Naito Foundation
- Waksman Foundation of Japan
- Yakult Bio-Science Foundation
- Yakult Central Institute
- Hayashi Memorial Foundation for Female Natural Scientists
- [23121525]
- [23000012]
- [23689027]
- [23790471]
- [23790472]
- [22790403]
- [23390102]
- [23659220]
- [18073003]
- Grants-in-Aid for Scientific Research [22790403, 22117001, 23770203, 23390102, 23121525, 23689027, 23790471, 23000012, 22117002] Funding Source: KAKEN
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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(1). Therefore, bacteria must modulate host inflammatory signalling and dampen these alarm signals(2-4.) How pathogens do this after invading epithelial cells remainsunclear, however. Herewe showthat OspI, a Shigella flexneri effector encoded by ORF169b on the large plasmid and delivered by the type III 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 diacylglycerolCBM (CARD-BCL10-MALT1) complex-TRAF6-nuclear-factorkB signalling pathway. We determined the 2.0 angstrom 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.
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