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.


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*


  • 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