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Publication : Flagellin-induced NLRC4 phosphorylation primes the inflammasome for activation by NAIP5.

First Author  Matusiak M Year  2015
Journal  Proc Natl Acad Sci U S A Volume  112
Issue  5 Pages  1541-6
PubMed ID  25605939 Mgi Jnum  J:217657
Mgi Id  MGI:5615293 Doi  10.1073/pnas.1417945112
Citation  Matusiak M, et al. (2015) Flagellin-induced NLRC4 phosphorylation primes the inflammasome for activation by NAIP5. Proc Natl Acad Sci U S A 112(5):1541-6
abstractText  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)-1beta 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-1beta secretion, and pyroptosis, suggesting that it retained Nlrc4 Ser533 phosphorylating-activity despite escaping Naip5 detection. In agreement, the flagellin D0 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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