期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 5, 页码 1541-1546出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1417945112
关键词
NLRC4; inflammasome; flagellin; caspase-1; Salmonella
资金
- Fund for Scientific Research-Flanders
- National Institute of Health [AR056296, CA163507, Al101935]
- American Lebanese Syrian Associated Charities (ALSAC)
- Ghent University [BOF 01N02313, 01J11113]
- Fund for Scientific Research-Flanders Grant [G030212N]
- European Research Council Grant [281600]
- European Research Council (ERC) [281600] Funding Source: European Research Council (ERC)
The Nlrc4 inflammasome contributes to immunity against intracellular pathogens that express flagellin and type III secretion systems, and activating mutations in NLRC4 cause autoinflammation in patients. Both Naip5 and phosphorylation of Nlrc4 at Ser533 are required for flagellin-induced inflammasome activation, but how these events converge upon inflammasome activation is not known. Here, we showed that Nlrc4 phosphorylation occurs independently of Naip5 detection of flagellin because Naip5 deletion in macrophages abolished caspase-1 activation, interleukin (IL)-1 beta secretion, and pyroptosis, but not Nlrc4 phosphorylation by cytosolic flagellin of Salmonella Typhimurium and Yersinia enterocolitica. ASC speck formation and caspase-1 expression also were dispensable for Nlrc4 phosphorylation. Interestingly, Helicobacter pylori flagellin triggered robust Nlrc4 phosphorylation, but failed to elicit caspase-1 maturation, IL-1 beta secretion, and pyroptosis, suggesting that it retained Nlrc4 Ser533 phosphorylatingactivity despite escaping Naip5 detection. In agreement, the flagellin Do domain was required and sufficient for Nlrc4 phosphorylation, whereas deletion of the S. Typhimurium flagellin carboxy-terminus prevented caspase-1 maturation only. Collectively, this work suggests a biphasic activation mechanism for the Nlrc4 inflammasome in which Ser533 phosphorylation prepares Nlrc4 for subsequent activation by the flagellin sensor Naip5.
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