期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：49
页码：E6790-E6797
DOI：10.1073/pnas.1508716112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe unfolded protein response (UPR) is a cellular mechanism for coping with misfolded proteins in the lumen of the endoplasmic reticulum (ER). UPR pathways are also induced in response to viral and bacterial pathogens, resulting in enhanced proinflammatory cytokine induction. Here we provide mechanistic evidence for how an intracellular pathogen is able to inhibit the IRE1 branch of the UPR by blocking host translation elongation. Given that a broad spectrum of pathogens block protein synthesis specifically at elongation rather than at other steps of translation, this may point to a common mechanism for blocking the UPR and thereby preventing enhanced proinflammatory cytokine signaling. Cells of the innate immune system recognize bacterial pathogens by detecting common microbial patterns as well as pathogen-specific activities. One system that responds to these stimuli is the IRE1 branch of the unfolded protein response (UPR), a sensor of endoplasmic reticulum (ER) stress. Activation of IRE1, in the context of Toll-like receptor (TLR) signaling, induces strong proinflammatory cytokine induction. We show here that Legionella pneumophila, an intravacuolar pathogen that replicates in an ER-associated compartment, blocks activation of the IRE1 pathway despite presenting pathogen products that stimulate this response. L. pneumophila TLR ligands induced the splicing of mRNA encoding XBP1s, the main target of IRE1 activity. L. pneumophila was able to inhibit both chemical and bacterial induction of XBP1 splicing via bacterial translocated proteins that interfere with host protein translation. A strain lacking five translocated translation elongation inhibitors was unable to block XBP1 splicing, but this could be rescued by expression of a single such inhibitor, consistent with limitation of the response by translation elongation inhibitors. Chemical inhibition of translation elongation blocked pattern recognition receptor-mediated XBP1 splicing, mimicking the effects of the bacterial translation inhibitors. In contrast, host cell-promoted inhibition of translation initiation in response to the pathogen was ineffective in blocking XBP1 splicing, demonstrating the need for the elongation inhibitors for protection from the UPR. The inhibition of host translation elongation may be a common strategy used by pathogens to limit the innate immune response by interfering with signaling via the UPR.
关键词：Legionella ; translation inhibition ; unfolded protein response
