Jan 15th: Damien ARNOULT
15 January 2020 @ 11 h 00 min - 12 h 00 min UTC+1
Damien ARNOULT, PhD
Directeur de Recherche,
INSERM U1197, Hôpital Paul Brousse
Title: A cytosolic unfolded protein response controls the scaffolding and signaling of innate immune complexes
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.
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Escalante NK, Trotman-Grant A, Lee JE, Gray-Owen SD, Divangahi M, Chen JJ, Philpott
DJ, Arnoult D*, Girardin SE. The heme-regulated inhibitor is a cytosolic sensor of protein
misfolding that controls innate immune signaling. Science. 2019 Jul 5;365(6448).
da Costa LS, Outlioua A, Anginot A, Akarid K, Arnoult D. RNA viruses promote activation
of the NLRP3 inflammasome through cytopathogenic effect-induced potassium efflux. Cell
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is a positive regulator of NF-κB activation. Cell Commun Signal. 2014 Nov 12;12(1):72.
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