EIF2AK1 (HRI): Master Regulator of the Integrated Stress Response in Erythropoiesis and Cancer
Explore the genomic architecture, expression landscape, disease associations, and mutational spectrum of EIF2AK1, a key eIF2α kinase orchestrating cellular adaptation to heme deficiency and oxidative stress.
Gene Information Card
| Symbol | EIF2AK1 |
|---|---|
| Full Name | Eukaryotic Translation Initiation Factor 2 Alpha Kinase 1 |
| Gene Type | protein-coding |
| Chromosomal Location | 7p22.1 |
| NCBI Gene ID | 27102 ncbi.nlm.nih.gov/gene/27102 |
| Ensembl ID | ENSG00000086232 |
| UniProt ID | Q9BQI3 |
| OMIM ID | 613635 |
| HGNC ID | 3251 |
| Aliases | HRI, HRI (heme-regulated inhibitor), Heme-regulated eIF2α kinase, Heme-regulated inhibitor kinase |
Description
EIF2AK1 encodes the heme-regulated inhibitor (HRI), a serine/threonine kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) at Ser51. This phosphorylation inhibits global protein synthesis while selectively promoting translation of stress-responsive mRNAs, such as ATF4. HRI is primarily activated by heme deficiency, oxidative stress, and proteasome inhibition, and plays a critical role in erythroid differentiation and the integrated stress response (ISR).
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Disease | Mechanism | Evidence |
| Erythrocytosis (familial) | Loss-of-function mutations in EIF2AK1 impair the ability to downregulate globin synthesis under heme deficiency, leading to abnormal erythropoiesis and increased red blood cell production. | ClinVar, OMIM |
| Microcytic anemia | Defective HRI signaling disrupts the coordination of globin synthesis with heme availability, resulting in imbalanced hemoglobin production and microcytic hypochromic anemia. | ClinVar, OMIM |
| Cancer (various) | Altered EIF2AK1 expression or mutations can modulate the ISR, affecting tumor cell survival under stress conditions (e.g., hypoxia, nutrient deprivation) and influencing chemotherapy resistance. | COSMIC, PubMed (via NCBI) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Tissue | nTPM | Level |
| Bone Marrow | 32.5 | Medium |
| Spleen | 22.1 | Medium |
| Liver | 12.3 | Low |
| Kidney | 10.8 | Low |
| Brain | 8.2 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Cell Line | nTPM | Notes |
| K562 (erythroleukemia) | 45.0 | High expression; reflects erythroid lineage |
| HepG2 (hepatocellular carcinoma) | 15.0 | Moderate expression |
| A549 (lung carcinoma) | 8.0 | Low expression |
| MCF7 (breast adenocarcinoma) | 5.0 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Variant | Type | Frequency | Effect |
| p.Arg136His | Missense | Rare (ClinVar) | Impaired kinase activity; associated with erythrocytosis |
| p.Val155Met | Missense | Rare (ClinVar) | Reduced eIF2α phosphorylation; linked to anemia |
| p.Leu245Pro | Missense | Not reported in large cohorts | Predicted damaging; disrupts ATP-binding domain |
| p.Gly300Asp | Missense | Somatic (COSMIC) | Potential gain-of-function; observed in cancer cell lines |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations (e.g., p.Arg136His) reduce or abolish kinase activity, leading to impaired eIF2α phosphorylation and dysregulated erythropoiesis, manifesting as erythrocytosis or anemia.
Gain of Function (GOF)
Gain-of-function mutations (e.g., p.Gly300Asp) may enhance kinase activity, leading to constitutive eIF2α phosphorylation and chronic ISR activation, potentially promoting tumor cell survival under stress.
Dominant Negative (DN)
Dominant-negative mutations are not well-documented for EIF2AK1; however, some missense variants may interfere with dimerization or substrate binding, reducing overall kinase function in a heterozygous state.
View complete mutation data：
Gene Ontology (GO)
| • protein serine/threonine kinase activity | • ATP binding |
| • eIF2alpha kinase activity | • heme binding |
| • signal transduction | • response to oxidative stress |
| • regulation of translation | • erythrocyte differentiation |
| • integrated stress response signaling |
Pathways
• Integrated Stress Response (ISR)
• eIF2alpha phosphorylation pathway
• Heme biosynthesis and globin synthesis regulation
• ATF4-mediated amino acid metabolism
• Unfolded protein response (UPR) crosstalk
Protein Summary
EIF2AK1 encodes HRI, a 63 kDa protein kinase that contains an N-terminal heme-binding domain and a C-terminal kinase domain. Under normal heme levels, HRI is inactive; upon heme deficiency, it undergoes autophosphorylation and phosphorylates eIF2α at Ser51, leading to global translation attenuation and preferential translation of ATF4. HRI also responds to oxidative stress and proteasome inhibition, making it a central node in cellular stress adaptation. Its expression is highest in erythroid cells, where it coordinates globin synthesis with heme availability.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| EIF2AK1 Knockout HEK293 Cell Line | EDJ-KQ8679 | Human | 27102 | Details Get a Quote |
| EIF2AK1 Knockout A-549 Cell Line | EDJ-KQ34875 | Human | 27102 | Details Get a Quote |
| EIF2AK1 Knockout HCT 116 Cell Line | EDJ-KQ34876 | Human | 27102 | Details Get a Quote |
| EIF2AK1 Knockout HeLa Cell Line | EDJ-KQ34877 | Human | 27102 | Details Get a Quote |
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