title: NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22.
abstract: 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.
authors.forename: Marianne R
authors.initials: MR
authors.lastname: Spalinger
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kasper
authors.forename: Claudia
authors.initials: C
authors.lastname: Gottier
authors.forename: Silvia
authors.initials: S
authors.lastname: Lang
authors.forename: Kirstin
authors.initials: K
authors.lastname: Atrott
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Vavricka
authors.forename: Sylvie
authors.initials: S
authors.lastname: Scharl
authors.forename: Tina
authors.initials: T
authors.lastname: Raselli
authors.forename: Isabelle
authors.initials: I
authors.lastname: Frey-Wagner
authors.forename: Petrus M
authors.initials: PM
authors.lastname: Gutte
authors.forename: Markus G
authors.initials: MG
authors.lastname: Grütter
authors.forename: Hans-Dietmar
authors.initials: HD
authors.lastname: Beer
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Contassot
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Chan
authors.forename: Xuezhi
authors.initials: X
authors.lastname: Dai
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
authors.forename: Florian
authors.initials: F
authors.lastname: Mair
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
authors.forename: Werner
authors.initials: W
authors.lastname: Falk
authors.forename: Michael
authors.initials: M
authors.lastname: Fried
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rogler
authors.forename: Michael
authors.initials: M
authors.lastname: Scharl
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003092:Colitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics / Q000378:metabolism*
chemical_list: C508585:IL1B protein, human; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516766:Ptpn22 protein, mouse