Advanced search
1 file | 1.36 MB

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

Author
Organization
Abstract
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.
Keywords
CELL-DEATH, IPAF, NEEDLE PROTEIN, IMMUNE RECOGNITION, INTERLEUKIN-1-BETA, CAUSES AUTOINFLAMMATION, CASPASE-1 AUTOPROTEOLYSIS, III SECRETION APPARATUS, Salmonella, caspase-1, flagellin, inflammasome, NLRC4, MUTATION, BACTERIA

Downloads

  • pnas.201417945.pdf
    • full text
    • |
    • open access
    • |
    • PDF
    • |
    • 1.36 MB

Citation

Please use this url to cite or link to this publication:

Chicago
Matusiak, Magdalena, Nina Van Opdenbosch, Lieselotte Vande Walle, Jean-Claude Sirard, Thirumala-Devi Kanneganti, and Mohamed Lamkanfi. 2015. “Flagellin-induced NLRC4 Phosphorylation Primes the Inflammasome for Activation by NAIP5.” Proceedings of the National Academy of Sciences of the United States of America 112 (5): 1541–1546.
APA
Matusiak, M., Van Opdenbosch, N., Vande Walle, L., Sirard, J.-C., Kanneganti, T.-D., & Lamkanfi, M. (2015). Flagellin-induced NLRC4 phosphorylation primes the inflammasome for activation by NAIP5. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 112(5), 1541–1546.
Vancouver
1.
Matusiak M, Van Opdenbosch N, Vande Walle L, Sirard J-C, Kanneganti T-D, Lamkanfi M. Flagellin-induced NLRC4 phosphorylation primes the inflammasome for activation by NAIP5. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2015;112(5):1541–6.
MLA
Matusiak, Magdalena, Nina Van Opdenbosch, Lieselotte Vande Walle, et al. “Flagellin-induced NLRC4 Phosphorylation Primes the Inflammasome for Activation by NAIP5.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 112.5 (2015): 1541–1546. Print.
@article{6966724,
  abstract     = {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.},
  author       = {Matusiak, Magdalena and Van Opdenbosch, Nina and Vande Walle, Lieselotte and Sirard, Jean-Claude and Kanneganti, Thirumala-Devi and Lamkanfi, Mohamed},
  issn         = {0027-8424},
  journal      = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
  keyword      = {CELL-DEATH,IPAF,NEEDLE PROTEIN,IMMUNE RECOGNITION,INTERLEUKIN-1-BETA,CAUSES AUTOINFLAMMATION,CASPASE-1 AUTOPROTEOLYSIS,III SECRETION APPARATUS,Salmonella,caspase-1,flagellin,inflammasome,NLRC4,MUTATION,BACTERIA},
  language     = {eng},
  number       = {5},
  pages        = {1541--1546},
  title        = {Flagellin-induced NLRC4 phosphorylation primes the inflammasome for activation by NAIP5},
  url          = {http://dx.doi.org/10.1073/pnas.1417945112},
  volume       = {112},
  year         = {2015},
}

Altmetric
View in Altmetric
Web of Science
Times cited: