biostudies-literatureOpaluch AMNIA NIH HHSNIAID NIH HHSNCI NIH HHSNIGMS NIH HHSPHS HHSe89284https://www.ebi.ac.uk/biostudies/studies/S-EPMC3930702biostudies-literatureUnknown9(2)Innate immune sensors such as Toll-like receptors (TLRs) differentially utilize adaptor proteins and additional molecular mediators to ensure robust and precise immune responses to pathogen challenge. Through a gain-of-function genetic screen, we identified the gamma catalytic subunit of protein phosphatase 1 (PP1-γ) as a positive regulator of MyD88-dependent proinflammatory innate immune activation. PP1-γ physically interacts with the E3 ubiquitin ligase TRAF6, and enhances the activity of TRAF6 towards itself and substrates such as IKKγ, whereas enzymatically inactive PP1-γ represses these events. Importantly, these activities were found to be critical for cellular innate responses to pathogen challenge and microbial clearance in both mouse macrophages and human monocyte lines. These data indicate that PP1-γ phosphatase activity regulates overall TRAF6 E3 ubiquitin ligase function and promotes NF-κB-mediated innate signaling responses.PloS onePositive regulation of TRAF6-dependent innate immune responses by protein phosphatase PP1-γ.PMC3930702AI777801 P50 NIGMS085764-01A2R21 AI096943R01 AI073450R01 AI089246R01 AI064001F31 AG032171AI0969431P01AI90935-01P30 CA030199R01 AI077780P50 GM085764P01 AI0909351R011AI073450-01A2Mulder LCKonig RMacLeod GMaestre AMOpaluch AMSchneider MSimon VDe Jesus PDChanda SKSecundino IChiang CYNguyen QTVarmuza SFernandez-Sesma ANizet VfalsePositive regulation of TRAF6-dependent innate immune responses by protein phosphatase PP1-γ.Innate immune sensors such as Toll-like receptors (TLRs) differentially utilize adaptor proteins and additional molecular mediators to ensure robust and precise immune responses to pathogen challenge. Through a gain-of-function genetic screen, we identified the gamma catalytic subunit of protein phosphatase 1 (PP1-γ) as a positive regulator of MyD88-dependent proinflammatory innate immune activation. PP1-γ physically interacts with the E3 ubiquitin ligase TRAF6, and enhances the activity of TRAF6 towards itself and substrates such as IKKγ, whereas enzymatically inactive PP1-γ represses these events. Importantly, these activities were found to be critical for cellular innate responses to pathogen challenge and microbial clearance in both mouse macrophages and human monocyte lines. These data indicate that PP1-γ phosphatase activity regulates overall TRAF6 E3 ubiquitin ligase function and promotes NF-κB-mediated innate signaling responses.2014-01-01T00:00:00Z20142024-11-19T21:39:28.927Z2019-03-26T23:23:48ZS-EPMC39307022458665910.1371/journal.pone.0089284