Flagellin-induced NLRC4 phosphorylation primes the inflammasome for activation by NAIP5
Abstract
The Nlrc4 inflammasome is critical for clearing bacterial infections and activating mutations in NLRC4 cause autoinflammation in patients. Here, we used genetic and biochemical approaches to show that Nlrc4 Ser533 phosphorylation by flagellin of Salmonella Typhimurium and Yersinia enterocolitica occurs upstream of Naip5 detection of flagellin, ASC speck formation and caspase-1 activation. We further showed that Helicobacter pylori flagellin triggered robust Nlrc4 phosphorylation but failed to elicit caspase-1 activation in agreement with the differential requirement for the Salmonella Typhimurium flagellin D0 domain and the carboxy-terminus for Ser533 phosphorylation and caspase-1 activation, respectively. Collectively, this work suggests a biphasic mechanism for Nlrc4 inflammasome activation in which Ser533 phosphorylation primes Nlrc4 for subsequent activation by Naip5.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- February 2015
- DOI:
- 10.1073/pnas.1417945112
- Bibcode:
- 2015PNAS..112.1541M