Spalinger, Marianne R. and Kasper, Stephanie and Gottier, Claudia and Lang, Silvia and Atrott, Kirstin and Vavricka, Stephan R. and Scharl, Sylvie and Gutte, Petrus M. and Grutter, Markus G. and Beer, Hans-Dietmar and Contassot, Emmanuel and Chan, Andrew C. and Dai, Xuezhi and Rawlings, David J. and Mair, Florian and Becher, Burkhard and Falk, Werner and Fried, Michael and Rogler, Gerhard and Scharl, Michael (2016) NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22. JOURNAL OF CLINICAL INVESTIGATION, 126 (5). pp. 1783-1800. ISSN 0021-9738, 1558-8238
Full text not available from this repository. (Request a copy)Abstract
Inflammasomes form as the result of the intracellular presence of danger-associated molecular patterns and mediate the release of active IL-1 beta, which influences a variety of inflammatory responses. Excessive inflammasome activation results in severe inflammatory conditions, but physiological IL-1 beta 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-1 beta release. In murine models, PTPN22 deficiency resulted in pronounced colitis, increased NLRP3 phosphorylation, but reduced levels of mature IL-1 beta. Conversely, patients with inflammatory bowel disease (IBD) that carried an autoimmunity-associated PTPN22 variant had increased IL-1 beta levels. Together, our results identify tyrosine phosphorylation as an important regulatory mechanism for NLRP3 that prevents aberrant inflammasome activation.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SYSTEMIC-LUPUS-ERYTHEMATOSUS; INFLAMMATORY-BOWEL-DISEASE; GENOME-WIDE ASSOCIATION; OF-FUNCTION VARIANT; REGULATORY T-CELLS; INTESTINAL INFLAMMATION; RHEUMATOID-ARTHRITIS; MICE; GENE; INFLAMMASOMES; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Mar 2019 12:08 |
| Last Modified: | 20 Mar 2019 12:08 |
| URI: | https://pred.uni-regensburg.de/id/eprint/3023 |
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