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

Abstract

<jats:p>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.</jats:p>

Developmentally regulated PERK activity renders dendritic cells insensitive to subtilase cytotoxin-induced integrated stress response

“…We found that mRNA translation in DCs, differently to what has been shown during chronic ISR , is mediated despite high p-eIF2α levels by an eIF4F-dependent mechanism. We also found that primary DCs, conversely to macrophages, do not rely on eIF2α phosphorylation to activate cytokines transcription nor IL-1β secretion in response to MAMPs (Abdel-Nour et al, 2019), (Chiritoiu et al, 2019). Importantly, GADD34 antagonizes PERK activity to maintain functional protein synthesis levels in non-activated DCs.…”

“…In macrophages, p-eIF2a-and ATF4-dependent expression of HSPB8 is required for the assembly of signaling adaptors such as mitochondrial antiviral-signaling protein (MAVS), or TIR domain-containing adapter protein inducing interferon-a (TRIF), but not of Myeloid Differentiation Primary Response Gene 88 (MyD88). HSPB8 seems necessary for TRIF and MAVS to be incorporated into protein aggregates that constitute signalosomes for different innate immunity signaling pathways triggered by MAMPs (Abdel-Nour et al, 2019). Given the lack of ATF4 synthesis and the resistance of active DCs to mount an acute ISR, we investigated their capacity to produce pro-inflammatory cytokines and type-I IFN in a perturbed eIF2a-phosphorylation context.…”

“…Several key innate immunity signaling cascades are believed to be dependent for their signalosome assembly on the chaperone HSPB8 and the kinase heme-regulated inhibitor (HRI/EIF2AK1) (Pierre, 2019). Microbe-activated HRI was shown to mediate phosphorylation of eIF2α and increase ATF4-dependent expression of HSPB8, thus promoting the signal transduction pathways leading to inflammatory cytokines transcription in macrophages (Abdel-Nour et al, 2019).…”

Translation of peptidoglycan metabolites into immunotherapeutics

“…Complex formation, stability and signal transduction are tightly controlled through numerous other proteins reviewed elsewhere . These regulatory mechanisms include the newly discovered role of heat‐shock protein B8 (HspB8), which directly binds to both Nod1 and Nod2, prevents their aggregation and may enhance the assembly of active Nod1/2 oligomers . In epithelial cells, Nod1/2 signalling leads to the cellular and tissue restriction of pathogens through induction of pathogen‐directed autophagy, or xenophagy, and the production of barrier‐promoting proteins and AMPs, respectively (Figures and ) .…”

“…16 These regulatory mechanisms include the newly discovered role of heat-shock protein B8 (HspB8), which directly binds to both Nod1 and Nod2, prevents their aggregation and may enhance the assembly of active Nod1/2 oligomers. 34 In epithelial cells, Nod1/2 signalling leads to the cellular and tissue restriction of pathogens through induction of pathogen-directed autophagy, or xenophagy, 35 and the production of barrier-promoting proteins and AMPs, respectively (Figures 2 and 3). 36,37 Moreover, activation of macrophages and other phagocytic myeloid cells elicits the direct killing of microbes and the clearance of host cells that present non-self signals from either internal pathogens or cancer-related mutations (Figures 2 and 3).…”