ArticleScience (New York, N.Y.)2019
The heme-regulated inhibitor is a cytosolic sensor of protein misfolding that controls innate immune signaling.
Article in Science (New York, N.Y.), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 117 citations in OpenAlex.
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- Integrated Stress Response Signatures Drive Monocyte Dysfunction in GBA1- and LRRK2-Linked Parkinson's Disease.Research square · 2026Article
- A central role for PINK1 in governing local mitochondrial biogenesis and degradation in neurons.Cellular and molecular life sciences : CMLS · 2026Review
- The role of ER-associated degradation and ER-phagy in health and disease.Signal transduction and targeted therapy · 2026Review
- Roles of the integrated stress response in regulation of inflammatory reactions.Frontiers in immunology · 2026Review
- Pharmacological targeting of RIG-I can selectively activate the integrated stress response.Science advances · 2025Article
- Integrated Stress Response Signatures Drive Monocyte Dysfunction inmedRxiv : the preprint server for health sciences · 2025Article
- Integrated stress response in Behçet disease: expression analyses in peripheral blood and synovial monocytes.Rheumatology international · 2025Article
- Plans within plans: post-transcriptional regulation governs macrophage responses.Trends in immunology · 2025Review
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- Transcriptomic signatures of oxytosis/ferroptosis are enriched in Alzheimer's disease.BMC biology · 2025Article
- HRI protein kinase in cytoplasmic heme sensing and mitochondrial stress response: Relevance to hematological and mitochondrial diseases.The Journal of biological chemistry · 2025Review
- Idiopathic Pulmonary Fibrosis Caused by Damaged Mitochondria and Imbalanced Protein Homeostasis in Alveolar Epithelial Type II Cell.Advanced biology · 2025Review
- Modulation of CREB3L2-ATF4 heterodimerization via proteasome inhibition and HRI activation in Alzheimer's disease pathology.Cell death & disease · 2025Article
- The integrated stress response in neurodegenerative diseases.Molecular neurodegeneration · 2025Review
- ROCK1 promotes B cell differentiation and proteostasis under stress through the heme-regulated proteins, BACH2 and HRI.JCI insight · 2025Article
- Stress Granules in Infectious Disease: Cellular Principles and Dynamic Roles in Immunity and Organelles.International journal of molecular sciences · 2024Review
- Why cells need iron: a compendium of iron utilisation.Trends in endocrinology and metabolism: TEM · 2024Review
16 more citing papers are in PubMed but not listed here.
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Authors and funding
23 authors at 4 institutions in 4 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.