| First Author | Abdel-Nour M | Year | 2019 |
| Journal | Science | Volume | 365 |
| Issue | 6448 | PubMed ID | 31273097 |
| Mgi Jnum | J:276778 | Mgi Id | MGI:6316600 |
| Doi | 10.1126/science.aaw4144 | Citation | Abdel-Nour M, et al. (2019) The heme-regulated inhibitor is a cytosolic sensor of protein misfolding that controls innate immune signaling. Science 365(6448) |
| abstractText | 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 eIF2alpha kinase heme-regulated inhibitor (HRI) controls NOD1 signalosome folding and activation through a process requiring eukaryotic initiation factor 2alpha (eIF2alpha), the transcription factor ATF4, and the heat shock protein HSPB8. The HRI/eIF2alpha 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 alpha-synuclein activated HRI-dependent responses, which suggests that the HRI pathway may restrict toxic oligomer formation. We propose that HRI, eIF2alpha, 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/eIF2alpha/HSPA5 axis of the endoplasmic reticulum UPR. |
