The heme-regulated inhibitor kinase Hri1 is activated in response to aminolevulinic acid deficiency in Schizosaccharomyces pombe.
A key mechanism for regulating the initiation of protein synthesis in response to various stresses involves the phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). Schizosaccharomyces pombe possesses three distinct eIF2α kinases: Hri1, Hri2, and Gcn2. Using a strain that is u...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2025-07-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1011797 |
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| Summary: | A key mechanism for regulating the initiation of protein synthesis in response to various stresses involves the phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). Schizosaccharomyces pombe possesses three distinct eIF2α kinases: Hri1, Hri2, and Gcn2. Using a strain that is unable to synthesize heme de novo (hem1Δ), global transcriptome analysis reveals that among the genes encoding these kinases, hri1+ is the most strongly induced under δ-aminolevulinate (ALA)-limiting conditions. The induction of hri1+ consistently correlates with increased eIF2α phosphorylation and a reduction in global protein translation in ALA-starved hem1Δ cells. In contrast, hem1Δ cells lacking hri1+ (hri1Δ) exhibit poor eIF2α phosphorylation under the same stress conditions. When ALA-starved hem1Δ hri1Δ cells are subsequently transferred to a medium supplemented with exogenous hemin, they exhibit impaired growth compared to ALA-starved hem1Δ cells expressing the endogenous hri1+ allele or hem1Δ hri1Δ hri2Δ gcn2Δ cells expressing functional hri1+ and hri1+-GFP alleles. Consistent with its role as a heme-sensing eIF2α kinase, further analysis by absorbance spectroscopy demonstrates that Hri1 binds to hemin, with an equilibrium dissociation constant (KD) of 0.11 µM. In contrast, a truncated form of Hri1 (from residues 1-185) fails to interact with hemin. Taken together, these findings provide the first report of a fungal eIF2α kinase being activated in response to stress directly linked to a defect in heme homeostasis. |
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| ISSN: | 1553-7390 1553-7404 |