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Jan 15th: Damien ARNOULT
15 January @ 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.
Abdel-Nour M, Carneiro LAM, Downey J, Tsalikis J, Outlioua A, Prescott D, Da Costa LS,
Hovingh ES, Farahvash A, Gaudet RG, Molinaro R, van Dalen R, Lau CCY, Azimi FC,
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
Death Dis. 2019 Apr 25;10(5):346.
Zemirli N, Pourcelot M, Dogan N, Vazquez A, Arnoult D. The E3 ubiquitin ligase RNF121
is a positive regulator of NF-κB activation. Cell Commun Signal. 2014 Nov 12;12(1):72.
Soares F, Tattoli I, Rahman MA, Robertson SJ, Belcheva A, Liu D, Streutker C, Winer S,
Winer DA, Martin A, Philpott DJ, Arnoult D, Girardin SE. The mitochondrial protein
NLRX1 controls the balance between extrinsic and intrinsic apoptosis. J Biol Chem. 2014 Jul