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

Mena Abdel-Nour; Leticia A M Carneiro; Jeffrey Downey; Jessica Tsalikis; Ahmed Outlioua; Dave Prescott; Leandro Silva Da Costa; Elise S Hovingh; Armin Farahvash; Ryan G Gaudet; Raphael Molinaro; Rob van Dalen; Charles C Y Lau; Farshad C Azimi; Nichole K Escalante; Aaron Trotman-Grant; Jeffrey E Lee; Scott D Gray-Owen; Maziar Divangahi; Jane-Jane Chen; Dana J Philpott; Damien Arnoult; Stephen E Girardin

doi:10.1126/science.aaw4144

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.

Authors

Mena Abdel-Nour¹, Leticia A M Carneiro¹, Jeffrey Downey², Jessica Tsalikis¹, Ahmed Outlioua^{3

4}, Dave Prescott^{1

5}, Leandro Silva Da Costa³, Elise S Hovingh¹, Armin Farahvash¹, Ryan G Gaudet⁶, Raphael Molinaro¹, Rob van Dalen¹, Charles C Y Lau^{1

5}, Farshad C Azimi¹, Nichole K Escalante⁵, Aaron Trotman-Grant⁵, Jeffrey E Lee¹, Scott D Gray-Owen⁶, Maziar Divangahi², Jane-Jane Chen⁷, Dana J Philpott⁵, Damien Arnoult³, Stephen E Girardin⁸

Affiliations

¹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
² Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
³ INSERM U1197, Hôpital Paul Brousse, Bâtiment Lavoisier, 94807 Villejuif Cedex, France.
⁴ Molecular Genetics and Immunophysiopathology Research Team, Health and Environment Laboratory, Aïn Chock Faculty of Sciences, Hassan II University of Casablanca, Casablanca, Morocco.
⁵ Department of Immunology, University of Toronto, Toronto, ON, Canada.
⁶ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁷ Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. [email protected] [email protected].

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*
Endoplasmic Reticulum Chaperone BiP
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
Endoplasmic Reticulum Chaperone BiP
Eukaryotic Initiation Factor-2
HSPA5 protein, human
Heat-Shock Proteins
Hspa5 protein, mouse
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

Grants and funding

R01 DK087984/DK/NIDDK NIH HHS/United States