Dataset Information

Positive regulation of TRAF6-dependent innate immune responses by protein phosphatase PP1-?.

ABSTRACT: 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-?) as a positive regulator of MyD88-dependent proinflammatory innate immune activation. PP1-? physically interacts with the E3 ubiquitin ligase TRAF6, and enhances the activity of TRAF6 towards itself and substrates such as IKK?, whereas enzymatically inactive PP1-? 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-? phosphatase activity regulates overall TRAF6 E3 ubiquitin ligase function and promotes NF-?B-mediated innate signaling responses.

SUBMITTER: Opaluch AM

PROVIDER: S-EPMC3930702 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Positive regulation of TRAF6-dependent innate immune responses by protein phosphatase PP1-γ.

Opaluch Amanda M AM Schneider Monika M Chiang Chih-yuan CY Nguyen Quy T QT Maestre Ana M AM Mulder Lubbertus C F LC Secundino Ismael I De Jesus Paul D PD König Renate R Simon Viviana V Nizet Victor V MacLeod Graham G Varmuza Susannah S Fernandez-Sesma Ana A Chanda Sumit K SK

PloS one 20140220 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 TRAF ...[more]

PMID: 24586659

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Project description:Pattern recognition receptors and receptors for pro-inflammatory cytokines provide critical signals to drive the development of protective immunity to infection. Therefore, counter-regulatory pathways are required to ensure that overwhelming inflammation harm host tissues. Previously, we showed that lipoxins modulate immune response during infection, restraining inflammation during infectious diseases in an Aryl hydrocarbon receptor (AhR)/suppressors of cytokine signaling (SOCS)2-dependent-manner. Recently, Indoleamine-pyrrole 2,3- dioxygenase (IDO)-derived tryptophan metabolites, including L-kynurenine, were also shown to be involved in several counter-regulatory mechanisms. Herein, we addressed whether the intracellular molecular events induced by lipoxins mediating control of innate immune signaling are part of a common regulatory pathway also shared by L-kynurenine exposure. We demonstrate that Tumor necrosis factor receptor-associated factor (TRAF)6--member of a family of adapter molecules that couple the TNF receptor and interleukin-1 receptor/Toll-like receptor families to intracellular signaling events essential for the development of immune responses--is targeted by both lipoxins and L-kynurenine via an AhR/SOCS2-dependent pathway. Furthermore, we show that LXA₄- and L-kynurenine-induced AhR activation, its subsequent nuclear translocation, leading SOCS2 expression and TRAF6 Lys47-linked poly-ubiquitination and proteosome-mediated degradation of the adapter proteins. The in vitro consequences of such molecular interactions included inhibition of TLR- and cytokine receptor-driven signal transduction and cytokine production. Subsequently, in vivo proteosome inhibition led to unresponsiveness to lipoxins, as well as to uncontrolled pro-inflammatory reactions and elevated mortality during toxoplasmosis. In summary, our results establish proteasome degradation of TRAF6 as a key molecular target for the anti-inflammatory pathway triggered by lipoxins and L-kynurenine, critical counter-regulatory mediators in the innate and adaptive immune systems.

Dataset Information

Positive regulation of TRAF6-dependent innate immune responses by protein phosphatase PP1-?.

Publications

Positive regulation of TRAF6-dependent innate immune responses by protein phosphatase PP1-γ.

Similar Datasets

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