Open AccessTBK1 and IKKε act like an OFF switch to limit NLRP3 inflammasome pathway activation
Author(s) -
Fabian A. Fischer,
Linda F. M. Mies,
Sohaib Nizami,
Eirini Pantazi,
Sara Danielli,
Benjamin Demarco,
Michael Ohlmeyer,
Michelle Sue Jann Lee,
Cevayir Coban,
Jonathan C. Kagan,
Elena Di Daniel,
Jelena S. Bezbradica
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2009309118
Subject(s) - iκb kinase , tank binding kinase 1 , inflammasome , protein phosphatase 2 , microbiology and biotechnology , kinase , serine , phosphorylation , chemistry , signal transduction , biology , phosphatase , protein kinase a , biochemistry , nf κb , map kinase kinase kinase , receptor
Significance The NLRP3 inflammasome is an innate sensor activated by signals released from pathogens or injured tissues. Activation of the NLRP3 inflammasome can be beneficial during infection and vaccination. Nonetheless, when NLRP3 activity is uncontrolled and chronic it becomes detrimental and contributes to inflammation-driven pathology in several diseases. Licensing mechanisms must exist that prevent unwanted NLRP3 inflammasome responses. Here, we characterize one such mechanism. We describe that TBK1 and IKKε, two closely related kinases activated upon TLR signaling, act as a novel OFF switch for the NLRP3 pathway. Using pharmacological and genetic approaches, we show that TBK1 and IKKε together limit the responses downstream of the NLRP3 inflammasome activation and work against the PP2A phosphatase ON switch to balance NLRP3 activity.