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

PLoS One. 2014 Feb 20;9(2):e89284. doi: 10.1371/journal.pone.0089284. eCollection 2014.

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-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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Dendritic Cells / microbiology
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunity, Innate*
  • Immunoprecipitation
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Mice
  • Mutation / genetics
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Protein Phosphatase 1 / physiology*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Streptococcal Infections / immunology*
  • Streptococcal Infections / metabolism
  • Streptococcal Infections / microbiology
  • Streptococcus / pathogenicity
  • TNF Receptor-Associated Factor 6 / antagonists & inhibitors
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism*
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / metabolism

Substances

  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • RNA, Messenger
  • RNA, Small Interfering
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptors
  • Ppp1cc protein, mouse
  • Protein Phosphatase 1