Journal Article

NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22

Rogler, Gerhard, Beer, Hans-Dietmar, Falk, Werner, Grütter, Markus G, Spalinger, Marianne R, Mair, Florian, Lang, Silvia, Frey-Wagner, Isabelle, Gutte, Petrus M, Fried, Michael, Chan, Andrew C, Becher, Burkhard, Raselli, Tina, Rawlings, David J, Kasper, Stephanie, Scharl, Michael, Scharl, Sylvie, Atrott, Kirstin, Contassot, Emmanuel, Gottier, Claudia, Dai, Xuezhi, Vavricka, Stephan R

2016

Overview

Inflammasomes form as the result of the intracellular presence of danger-associated molecular patterns and mediate the release of active IL-1β, which influences a variety of inflammatory responses. Excessive inflammasome activation results in severe inflammatory conditions, but physiological IL-1β secretion is necessary for intestinal homeostasis. Here, we have described a mechanism of NLRP3 inflammasome regulation by tyrosine phosphorylation of NLRP3 at Tyr861. We demonstrated that protein tyrosine phosphatase non-receptor 22 (PTPN22), variants in which are associated with chronic inflammatory disorders, dephosphorylates NLRP3 upon inflammasome induction, allowing efficient NLRP3 activation and subsequent IL-1β release. In murine models, PTPN22 deficiency resulted in pronounced colitis, increased NLRP3 phosphorylation, but reduced levels of mature IL-1β. Conversely, patients with inflammatory bowel disease (IBD) that carried an autoimmunity-associated PTPN22 variant had increased IL-1β levels. Together, our results identify tyrosine phosphorylation as an important regulatory mechanism for NLRP3 that prevents aberrant inflammasome activation.

• Publisher: American Society for Clinical Investigation
• Subject: Analysis / Animals / Apoptosis / Biomedical research / Cell culture / Cell Line, Tumor / Colitis - genetics / Colitis - metabolism / Colitis - pathology / Colleges & universities / Cytokines / Data analysis / Disease / Disease Models, Animal / Experiments / Grants / Humans / Inflammation / Inflammatory bowel disease / Inflammatory Bowel Diseases - genetics / Inflammatory Bowel Diseases - metabolism / Inflammatory Bowel Diseases - pathology / Interleukin-1beta - genetics / Interleukin-1beta - metabolism / Ligands / Mice / NLR Family, Pyrin Domain-Containing 3 Protein - genetics / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / Patients / Phosphatase / Phosphorylation / Phosphorylation - genetics / Protein Tyrosine Phosphatase, Non-Receptor Type 22 - genetics / Protein Tyrosine Phosphatase, Non-Receptor Type 22 - metabolism / Proteins / Tyrosine