The heme-regulated inhibitor is a cytosolic sensor of protein misfolding that controls innate immune signaling

Science. 2019 Jul 5;365(6448):eaaw4144. doi: 10.1126/science.aaw4144.

Abstract

Multiple cytosolic innate sensors form large signalosomes after activation, but this assembly needs to be tightly regulated to avoid accumulation of misfolded aggregates. We found that the eIF2α kinase heme-regulated inhibitor (HRI) controls NOD1 signalosome folding and activation through a process requiring eukaryotic initiation factor 2α (eIF2α), the transcription factor ATF4, and the heat shock protein HSPB8. The HRI/eIF2α signaling axis was also essential for signaling downstream of the innate immune mediators NOD2, MAVS, and TRIF but dispensable for pathways dependent on MyD88 or STING. Moreover, filament-forming α-synuclein activated HRI-dependent responses, which suggests that the HRI pathway may restrict toxic oligomer formation. We propose that HRI, eIF2α, and HSPB8 define a novel cytosolic unfolded protein response (cUPR) essential for optimal innate immune signaling by large molecular platforms, functionally homologous to the PERK/eIF2α/HSPA5 axis of the endoplasmic reticulum UPR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Cell Line
  • Cytosol / enzymology*
  • Cytosol / immunology*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Fibroblasts
  • Heat-Shock Proteins / metabolism
  • Humans
  • Immunity, Innate*
  • Listeria / immunology
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Mutant Strains
  • Molecular Chaperones / metabolism
  • Myeloid Differentiation Factor 88 / metabolism
  • Nod1 Signaling Adaptor Protein / chemistry
  • Nod1 Signaling Adaptor Protein / metabolism
  • Nod2 Signaling Adaptor Protein / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Salmonella / immunology
  • Salmonella Infections
  • Shigella / immunology
  • Signal Transduction
  • Unfolded Protein Response / immunology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Atf4 protein, mouse
  • Eukaryotic Initiation Factor-2
  • Heat-Shock Proteins
  • Hspb8 protein, mouse
  • IPS-1 protein, mouse
  • Membrane Proteins
  • Molecular Chaperones
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Nod1 Signaling Adaptor Protein
  • Nod1 protein, mouse
  • Nod2 Signaling Adaptor Protein
  • Nod2 protein, mouse
  • Sting1 protein, mouse
  • TICAM-1 protein, mouse
  • Activating Transcription Factor 4
  • Protein-Serine-Threonine Kinases
  • eIF2alpha kinase, mouse

Grant support