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...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2025-07-01
|
| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1011797 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849706749988175872 |
|---|---|
| author | Samuel Plante Ariane Brault Mariano Avino Hajer Sakouhi Florie Lo Ying Ping Tobias Vahsen Simon Labbé |
| author_facet | Samuel Plante Ariane Brault Mariano Avino Hajer Sakouhi Florie Lo Ying Ping Tobias Vahsen Simon Labbé |
| author_sort | Samuel Plante |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6431c01ec07d4688bb93d4753344c7c0 |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-6431c01ec07d4688bb93d4753344c7c02025-08-20T03:16:06ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042025-07-01217e101179710.1371/journal.pgen.1011797The heme-regulated inhibitor kinase Hri1 is activated in response to aminolevulinic acid deficiency in Schizosaccharomyces pombe.Samuel PlanteAriane BraultMariano AvinoHajer SakouhiFlorie Lo Ying PingTobias VahsenSimon LabbéA 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.https://doi.org/10.1371/journal.pgen.1011797 |
| spellingShingle | Samuel Plante Ariane Brault Mariano Avino Hajer Sakouhi Florie Lo Ying Ping Tobias Vahsen Simon Labbé The heme-regulated inhibitor kinase Hri1 is activated in response to aminolevulinic acid deficiency in Schizosaccharomyces pombe. PLoS Genetics |
| title | The heme-regulated inhibitor kinase Hri1 is activated in response to aminolevulinic acid deficiency in Schizosaccharomyces pombe. |
| title_full | The heme-regulated inhibitor kinase Hri1 is activated in response to aminolevulinic acid deficiency in Schizosaccharomyces pombe. |
| title_fullStr | The heme-regulated inhibitor kinase Hri1 is activated in response to aminolevulinic acid deficiency in Schizosaccharomyces pombe. |
| title_full_unstemmed | The heme-regulated inhibitor kinase Hri1 is activated in response to aminolevulinic acid deficiency in Schizosaccharomyces pombe. |
| title_short | The heme-regulated inhibitor kinase Hri1 is activated in response to aminolevulinic acid deficiency in Schizosaccharomyces pombe. |
| title_sort | heme regulated inhibitor kinase hri1 is activated in response to aminolevulinic acid deficiency in schizosaccharomyces pombe |
| url | https://doi.org/10.1371/journal.pgen.1011797 |
| work_keys_str_mv | AT samuelplante thehemeregulatedinhibitorkinasehri1isactivatedinresponsetoaminolevulinicaciddeficiencyinschizosaccharomycespombe AT arianebrault thehemeregulatedinhibitorkinasehri1isactivatedinresponsetoaminolevulinicaciddeficiencyinschizosaccharomycespombe AT marianoavino thehemeregulatedinhibitorkinasehri1isactivatedinresponsetoaminolevulinicaciddeficiencyinschizosaccharomycespombe AT hajersakouhi thehemeregulatedinhibitorkinasehri1isactivatedinresponsetoaminolevulinicaciddeficiencyinschizosaccharomycespombe AT florieloyingping thehemeregulatedinhibitorkinasehri1isactivatedinresponsetoaminolevulinicaciddeficiencyinschizosaccharomycespombe AT tobiasvahsen thehemeregulatedinhibitorkinasehri1isactivatedinresponsetoaminolevulinicaciddeficiencyinschizosaccharomycespombe AT simonlabbe thehemeregulatedinhibitorkinasehri1isactivatedinresponsetoaminolevulinicaciddeficiencyinschizosaccharomycespombe AT samuelplante hemeregulatedinhibitorkinasehri1isactivatedinresponsetoaminolevulinicaciddeficiencyinschizosaccharomycespombe AT arianebrault hemeregulatedinhibitorkinasehri1isactivatedinresponsetoaminolevulinicaciddeficiencyinschizosaccharomycespombe AT marianoavino hemeregulatedinhibitorkinasehri1isactivatedinresponsetoaminolevulinicaciddeficiencyinschizosaccharomycespombe AT hajersakouhi hemeregulatedinhibitorkinasehri1isactivatedinresponsetoaminolevulinicaciddeficiencyinschizosaccharomycespombe AT florieloyingping hemeregulatedinhibitorkinasehri1isactivatedinresponsetoaminolevulinicaciddeficiencyinschizosaccharomycespombe AT tobiasvahsen hemeregulatedinhibitorkinasehri1isactivatedinresponsetoaminolevulinicaciddeficiencyinschizosaccharomycespombe AT simonlabbe hemeregulatedinhibitorkinasehri1isactivatedinresponsetoaminolevulinicaciddeficiencyinschizosaccharomycespombe |