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

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

Author information

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. stephen.girardin@utoronto.ca damien.arnoult@inserm.fr.

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.

PMID:
31273097
DOI:
10.1126/science.aaw4144

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