EIF2AK1 (heme-regulated inhibitor, HRI) is a cytosolic serine/threonine kinase of the eIF2alpha kinase family that phosphorylates eIF2alpha (EIF2S1) on Ser51, attenuating global cap-dependent translation while promoting translation of ISR mRNAs such as ATF4. HRI is most abundant in erythroid precursors, where its N-terminal and kinase-insert heme-binding domains sense intracellular heme: heme keeps the kinase inactive, and heme deficiency relieves inhibition and triggers autophosphorylation, so that globin synthesis is matched to heme availability and erythroid cells survive iron deficiency. HRI is also activated by oxidative and other cytoplasmic stresses, and is the eIF2alpha kinase that relays mitochondrial stress to the cytosol: the OMA1-cleaved C-terminal fragment of DELE1, or full-length DELE1 stabilized on the mitochondrial surface under iron limitation, binds and activates HRI. The HRI branch of the integrated stress response additionally drives PINK1/PRKN-independent mitophagy through mitochondrial accumulation of phospho-eIF2, and has been implicated in a cytosolic protein-folding response supporting innate immune signalosome assembly.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004672 protein kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic protein kinase activity from ARBA/InterPro. Reason: Correct, though less specific than eIF2alpha kinase activity. Supporting Evidence: file:human/EIF2AK1/EIF2AK1-uniprot.txt Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000003 | ACCEPT | Summary: EC 2.7.11.1 mapping to protein serine/threonine kinase activity. Reason: Correct; HRI phosphorylates eIF2alpha Ser51 and autophosphorylates. Supporting Evidence: file:human/EIF2AK1/EIF2AK1-uniprot.txt Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA: eIF2alpha kinase activity across the eIF2AK family. Reason: Correct and core; human HRI is among the experimental sources. Supporting Evidence: file:human/EIF2AK1/EIF2AK1-uniprot.txt Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions PMID:38340717 HRI phosphorylates the EIF2Ξ± subunit of the trimeric translation initiation factor EIF2. |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IDA PMID:11036079 Hsp90 regulates p50(cdc37) function during the biogenesis of... | ACCEPT | Summary: HRI activation/eIF2alpha kinase activity in reticulocyte lysate, promoted by HSP90-CDC37 during biogenesis. Reason: Abstract-only cache; defer to the curator for the assay details. The activity itself is well established. Supporting Evidence: PMID:11036079 p50(cdc37) stimulated HRI's activation in response to heme deficiency, but did not activate HRI per se. |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IDA PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | ACCEPT | Summary: Cytosolic DELE1 short form activates HRI eIF2alpha kinase activity. Reason: Core activity. Supporting Evidence: PMID:32132706 Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: Purified DELE1 stimulates eIF2alpha kinase activity of purified HRI in vitro. Reason: Direct biochemical evidence; core. Supporting Evidence: PMID:32132707 Using purified HRI, eIF2Ξ± and DELE1, we showed that DELE1 stimulates eIF2Ξ± kinase activity of HRI in vitro |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IDA PMID:37550454 DELE1 oligomerization promotes integrated stress response ac... | ACCEPT | Summary: Oligomeric DELE1-CTD activates HRI kinase activity. Reason: Core activity. Supporting Evidence: PMID:37550454 Mitochondrial stress activates the inner mitochondrial membrane protease OMA1, which promotes cleavage of DELE1, resulting in an accumulation of the DELE1 carboxy-terminal domain (DELE1CTD) in the cytosol, where it activates the HRI kinase. |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IDA PMID:38340717 The HRI branch of the integrated stress response selectively... | ACCEPT | Summary: HRI phosphorylates eIF2alpha to trigger mitophagy. Reason: Core activity. Supporting Evidence: PMID:38340717 HRI phosphorylates the EIF2Ξ± subunit of the trimeric translation initiation factor EIF2. |
| GO:0005515 protein binding | IPI PMID:22939624 Quantitative analysis of HSP90-client interactions reveals p... | REMOVE | Summary: Quantitative HSP90 client interaction screen detected HRI with HSP90AA1. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe HRI activity. HRI is an HSP90-CDC37 client kinase. Supporting Evidence: PMID:22939624 Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. |
| GO:0005515 protein binding | IPI PMID:29568061 An AP-MS- and BioID-compatible MAC-tag enables comprehensive... | REMOVE | Summary: AP-MS/BioID interaction with HSPA8. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe HRI activity. Supporting Evidence: PMID:29568061 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. |
| GO:0005515 protein binding | IPI PMID:31273097 The heme-regulated inhibitor is a cytosolic sensor of protei... | REMOVE | Summary: HRI interaction with HSPA8 in the cytosolic unfolded protein response study. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe HRI activity. Supporting Evidence: PMID:31273097 We propose that HRI, eIF2Ξ±, and HSPB8 define a novel cytosolic unfolded protein response (cUPR) essential for optimal innate immune signaling by large molecular platforms |
| GO:0005515 protein binding | IPI PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | REMOVE | Summary: HRI binds the DELE1 short form. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe HRI activity. The functional consequence (DELE1-dependent activation) is captured by HRI-mediated signaling and kinase activity rows; GO has no informative 'activator-bound' MF for the target kinase. Supporting Evidence: PMID:32132706 Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. |
| GO:0005515 protein binding | IPI PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | REMOVE | Summary: HRI interacts with cytosolic DELE1. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe HRI activity. Functional content captured elsewhere. Supporting Evidence: PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | REMOVE | Summary: Kinase interaction network: HRI with HSP90AA1. Reason: Generic protein binding is uninformative; the interaction is not disputed but does not describe HRI activity. Supporting Evidence: PMID:32707033 Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro: protein kinase ATP-binding. Reason: Correct for an active kinase. Supporting Evidence: file:human/EIF2AK1/EIF2AK1-uniprot.txt Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) |
| GO:0005634 nucleus | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: PAINT IBA for nucleus at a broad protein-kinase ancestral node. Reason: HRI acts on cytosolic eIF2 and is activated by cytosolic DELE1; there is no evidence that nuclear HRI performs a function. The node spans diverse kinases with nuclear roles, so propagation of 'is_active_in nucleus' to HRI is not well supported, although HPA reports some nucleoplasmic staining. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000113601 SUPPORTS SOURCE BUT NOT TARGET Deep protein-kinase ancestral node whose nuclear IBD is grounded in kinases with nuclear functions; the HRI lineage acts on cytosolic eIF2 and is activated by cytosolic DELE1. UniProtKB:P19525 Β· EIF2AK2 SUPPORTS SOURCE BUT NOT TARGET PKR has reported nuclear pools; this does not establish a nuclear site of activity for HRI. Supporting Evidence: file:human/EIF2AK1/EIF2AK1-uniprot.txt Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Human Protein Atlas immunofluorescence: nucleoplasm. Reason: Observed localization; not the site of known HRI activity. Supporting Evidence: file:human/EIF2AK1/EIF2AK1-uniprot.txt Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA: cytoplasm is the site of eIF2AK activity. Reason: Correct. Supporting Evidence: PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer of cytoplasm from mouse. Reason: Correct. Supporting Evidence: PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas: cytosol. Reason: Correct. Supporting Evidence: PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. |
| GO:0005829 cytosol | IDA PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | ACCEPT | Summary: DELE1 activates HRI in the cytosol. Reason: Correct site of activity. Supporting Evidence: PMID:32132706 Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. |
| GO:0005829 cytosol | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: DELE1 interacts with and activates HRI in the cytosol. Reason: Correct site of activity. Supporting Evidence: PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9840429 | ACCEPT | Summary: Reactome: DELE1(143-515) binds HRI in the cytosol. Reason: Correct. Supporting Evidence: Reactome:R-HSA-9840429 The C-terminal fragment of cleaved DELE1 interacts with EIF2AK1 (HRI) in the cytosol |
| GO:0006446 regulation of translational initiation | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA: regulation of translational initiation. Reason: Correct; eIF2alpha phosphorylation inhibits ternary complex recycling and thereby translation initiation. Supporting Evidence: PMID:31554636 Heme-regulated eIF2Ξ± kinase, also known as heme-regulated inhibitor (HRI), is a key heme-binding protein that senses intracellular heme concentrations to balance globin protein synthesis with the amount of heme available for hemoglobin production. |
| GO:0006446 regulation of translational initiation | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA: regulation of translational initiation. Reason: Correct. Supporting Evidence: PMID:31554636 Heme-regulated eIF2Ξ± kinase, also known as heme-regulated inhibitor (HRI), is a key heme-binding protein that senses intracellular heme concentrations to balance globin protein synthesis with the amount of heme available for hemoglobin production. |
| GO:0006950 response to stress | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA: response to stress. Reason: Correct but very general; HRI-mediated signaling is the informative term. Supporting Evidence: file:human/EIF2AK1/EIF2AK1-uniprot.txt Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions |
| GO:0008285 negative regulation of cell population proliferation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl transfer from mouse: negative regulation of cell population proliferation. Reason: A generic consequence of global translation attenuation; not a specific HRI role described for human HRI. Supporting Evidence: file:human/EIF2AK1/EIF2AK1-uniprot.txt Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions |
| GO:0020037 heme binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer of heme binding from mouse HRI. Reason: Heme binding to the N-terminal and kinase-insert domains is the defining regulatory property of HRI. Supporting Evidence: PMID:31554636 Heme-regulated eIF2Ξ± kinase, also known as heme-regulated inhibitor (HRI), is a key heme-binding protein that senses intracellular heme concentrations to balance globin protein synthesis with the amount of heme available for hemoglobin production. PMID:14672943 two histidine residues have been identified that are crucial for the binding of heme to the NTD. |
| GO:0020037 heme binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse HRI: heme binding. Reason: Core regulatory property (heme sensing). Supporting Evidence: file:human/EIF2AK1/EIF2AK1-uniprot.txt Acts as a key sensor of heme-deficiency: in normal conditions, binds hemin via a cysteine thiolate and histidine nitrogenous coordination, leading to inhibit the protein kinase activity (By similarity). PMID:17110456 In this manner, HRI serves as a feedback inhibitor of globin synthesis by sensing the intracellular concentration of heme through its heme-binding domains. |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer: protein homodimerization activity. Reason: HRI forms (disulfide-linked) homodimers; dimerization is part of the activation/inhibition mechanism but not its functional output. Supporting Evidence: file:human/EIF2AK1/EIF2AK1-uniprot.txt Inhibited by heme: in presence of heme, forms a disulfide-linked inactive homodimer (By similarity). Heme depletion relieves inhibition and stimulates kinase activity by autophosphorylation. |
| GO:0042803 protein homodimerization activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: protein homodimerization activity. Reason: As above. Supporting Evidence: file:human/EIF2AK1/EIF2AK1-uniprot.txt Inhibited by heme: in presence of heme, forms a disulfide-linked inactive homodimer (By similarity). Heme depletion relieves inhibition and stimulates kinase activity by autophosphorylation. |
| GO:0045993 negative regulation of translational initiation by iron | NAS PMID:11036079 Hsp90 regulates p50(cdc37) function during the biogenesis of... | ACCEPT | Summary: Author statement that HRI inhibits translation initiation in heme/iron deficiency. Reason: Classic HRI function in erythroid precursors. Supporting Evidence: PMID:11036079 p50(cdc37) stimulated HRI's activation in response to heme deficiency, but did not activate HRI per se. PMID:17110456 In this manner, HRI serves as a feedback inhibitor of globin synthesis by sensing the intracellular concentration of heme through its heme-binding domains. |
| GO:0046777 protein autophosphorylation | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse: autophosphorylation. Reason: Heme depletion stimulates HRI kinase activity by autophosphorylation; correct activation step. Supporting Evidence: file:human/EIF2AK1/EIF2AK1-uniprot.txt Inhibited by heme: in presence of heme, forms a disulfide-linked inactive homodimer (By similarity). Heme depletion relieves inhibition and stimulates kinase activity by autophosphorylation. |
| GO:0046986 negative regulation of hemoglobin biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl: negative regulation of hemoglobin biosynthetic process. Reason: Well-established physiological role: HRI balances globin synthesis with heme availability. Supporting Evidence: PMID:17110456 In this manner, HRI serves as a feedback inhibitor of globin synthesis by sensing the intracellular concentration of heme through its heme-binding domains. file:human/EIF2AK1/EIF2AK1-uniprot.txt In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties (By similarity). |
| GO:0046986 negative regulation of hemoglobin biosynthetic process | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse: negative regulation of hemoglobin biosynthetic process. Reason: As above. Supporting Evidence: PMID:17110456 In this manner, HRI serves as a feedback inhibitor of globin synthesis by sensing the intracellular concentration of heme through its heme-binding domains. |
| GO:0070585 protein localization to mitochondrion | IDA PMID:38340717 The HRI branch of the integrated stress response selectively... | KEEP AS NON CORE | Summary: HRI activity causes phospho-eIF2 to accumulate on mitochondria. Reason: HRI phosphorylates eIF2alpha; relocalization of phospho-eIF2 to mitochondria is a downstream consequence. Accepting the curator's experimental call, but this is not a direct HRI activity. Supporting Evidence: PMID:38340717 HRI activation results in accumulation of phosphorylated EIF2 on mitochondria, and we show that this localization is sufficient to trigger mitophagy. |
| GO:0106310 protein serine kinase activity | EXP PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: HRI phosphorylates eIF2alpha serine 51. Reason: Correct; more specific term GO:0004694 also present. Supporting Evidence: PMID:32132707 Using purified HRI, eIF2Ξ± and DELE1, we showed that DELE1 stimulates eIF2Ξ± kinase activity of HRI in vitro |
| GO:0106310 protein serine kinase activity | EXP PMID:38340717 The HRI branch of the integrated stress response selectively... | ACCEPT | Summary: HRI phosphorylates eIF2alpha in the mitophagy pathway. Reason: Correct. Supporting Evidence: PMID:38340717 HRI phosphorylates the EIF2Ξ± subunit of the trimeric translation initiation factor EIF2. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea-based protein serine kinase activity. Reason: Correct. Supporting Evidence: file:human/EIF2AK1/EIF2AK1-uniprot.txt Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) |
| GO:0140467 integrated stress response signaling | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: HRI relays mitochondrial stress to ATF4 (ISR). Reason: Correct; parent of HRI-mediated signaling. Supporting Evidence: PMID:32132707 HRI is the eIF2Ξ± kinase that is necessary and sufficient for this relay. |
| GO:0140468 HRI-mediated signaling | IDA PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | ACCEPT | Summary: OMA1-DELE1-HRI pathway. Reason: Core process. Supporting Evidence: PMID:32132706 Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. |
| GO:0140468 HRI-mediated signaling | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: HRI is necessary and sufficient for mitochondrial-stress ISR relay. Reason: Core process. Supporting Evidence: PMID:32132707 HRI is the eIF2Ξ± kinase that is necessary and sufficient for this relay. |
| GO:0140468 HRI-mediated signaling | IDA PMID:37550454 DELE1 oligomerization promotes integrated stress response ac... | ACCEPT | Summary: DELE1 oligomers activate HRI-dependent ISR. Reason: Core process. Supporting Evidence: PMID:37550454 Mitochondrial stress activates the inner mitochondrial membrane protease OMA1, which promotes cleavage of DELE1, resulting in an accumulation of the DELE1 carboxy-terminal domain (DELE1CTD) in the cytosol, where it activates the HRI kinase. |
| GO:0140468 HRI-mediated signaling | IDA PMID:38340717 The HRI branch of the integrated stress response selectively... | ACCEPT | Summary: HRI branch of the ISR in mitochondrial damage. Reason: Core process. Supporting Evidence: PMID:38340717 Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. |
| GO:1901526 positive regulation of mitophagy | IDA PMID:38340717 The HRI branch of the integrated stress response selectively... | KEEP AS NON CORE | Summary: HRI branch selectively induces mitophagy via mitochondrial phospho-eIF2. Reason: Supported; a regulatory output of HRI kinase activity, distinct from its core translational-control role. Supporting Evidence: PMID:38340717 Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. PMID:38340717 HRI activation results in accumulation of phosphorylated EIF2 on mitochondria, and we show that this localization is sufficient to trigger mitophagy. |
| GO:1990641 response to iron ion starvation | IDA PMID:11036079 Hsp90 regulates p50(cdc37) function during the biogenesis of... | ACCEPT | Summary: HRI activation in heme deficiency (reticulocyte lysate). Reason: Supported more directly for iron deficiency by DELE1-dependent HRI activation (PMID:37327776) and by the erythroid HRI literature. Supporting Evidence: PMID:11036079 p50(cdc37) stimulated HRI's activation in response to heme deficiency, but did not activate HRI per se. PMID:37327776 Here, we show that iron-deficiency-induced HRI activation requires the mitochondrial protein DELE1. |
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Download this section (compressed HTML)Q: How do heme sensing and DELE1 binding interact structurally in HRI β does DELE1 activation override heme-mediated inhibition, and is this important in non-erythroid tissues?
Q: Is HRI a bona fide sensor of cytosolic protein misfolding (cUPR), and if so what molecular feature of misfolded proteins does it detect?
Experiment: Reconstitute purified HRI with DELE1-CTD oligomers across heme concentrations and measure autophosphorylation and eIF2alpha phosphorylation; map binding sites by crosslinking-MS or cryo-EM.
Hypothesis: DELE1-CTD and heme bind distinct HRI sites and act antagonistically on kinase activation.
Type: biochemical reconstitution / structural biology
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