A cytosolic unfolded protein response controls innate immune signaling
Multiple cytosolic innate sensors form large oligomers following activation, yet this assembly needs to be tightly regulated to avoid accumulation of misfolded aggregates. We observed that the eIF2α kinase of the highly conserved integrated stress response (ISR) pathway, heme-regulated inhibitor (HRI), controlled the oligomerization of Nod1 and Nod2, and was essential for innate signaling by these bacterial sensors. In vivo, HRI- deficient mice displayed blunted responses to intraperitoneal injection of Nod ligands and were susceptible to intragastric infection with Citrobacter rodentium. We identified HSPB8 as an HRI-induced chaperone that mediated the effects of HRI by interacting with Nod1 and Nod2, thereby preventing aggregation of Nod signalosomes. Furthermore, HRI licensed activation of multiple innate immune signaling pathways that require oligomerization, such as MAVS, TIFA and NLRP3, but was dispensable for oligomerization-independent sensors, including STING and Toll-like receptors (TLRs). More generally, HRI was essential to limit proteotoxic stress induced by proteasome inhibition, and to prevent á-synuclein aggregation, showing that HRI acts as a general sensor of cytosolic protein misfolding. Thus, HRI, eIF2α and HSPB8 define a novel cytosolic unfolded protein response (cUPR) functionally homologous to the PERK/eIF2α/HSPA5 axis of the endoplasmic reticulum UPR. We propose that the cUPR is a critical protein surveillance system that controls cytosolic protein oligomerization and innate immune signaling, which may represent a druggable target for inflammatory diseases and pathologies displaying cytotoxic protein aggregation.
Chargé de Recherche
INSERM U542, Hopital Paul Brousse, Universite Paris Sud