The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicans.
Protein kinases play central roles in virtually all signaling pathways that enable organisms to adapt to their environment. Microbial pathogens must cope with severely restricted iron availability in mammalian hosts to invade and establish themselves within infected tissues. To uncover protein kinas...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-02-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1010283 |
| _version_ | 1818908803001745408 |
|---|---|
| author | Bernardo Ramírez-Zavala Ines Krüger Christine Dunker Ilse D Jacobsen Joachim Morschhäuser |
| author_facet | Bernardo Ramírez-Zavala Ines Krüger Christine Dunker Ilse D Jacobsen Joachim Morschhäuser |
| author_sort | Bernardo Ramírez-Zavala |
| collection | DOAJ |
| description | Protein kinases play central roles in virtually all signaling pathways that enable organisms to adapt to their environment. Microbial pathogens must cope with severely restricted iron availability in mammalian hosts to invade and establish themselves within infected tissues. To uncover protein kinase signaling pathways that are involved in the adaptation of the pathogenic yeast Candida albicans to iron limitation, we generated a comprehensive protein kinase deletion mutant library of a wild-type strain. Screening of this library revealed that the protein kinase Ire1, which has a conserved role in the response of eukaryotic cells to endoplasmic reticulum stress, is essential for growth of C. albicans under iron-limiting conditions. Ire1 was not necessary for the activity of the transcription factor Sef1, which regulates the response of the fungus to iron limitation, and Sef1 target genes that are induced by iron depletion were normally upregulated in ire1Δ mutants. Instead, Ire1 was required for proper localization of the high-affinity iron permease Ftr1 to the cell membrane. Intriguingly, iron limitation did not cause increased endoplasmic reticulum stress, and the transcription factor Hac1, which is activated by Ire1-mediated removal of the non-canonical intron in the HAC1 mRNA, was dispensable for Ftr1 localization to the cell membrane and growth under iron-limiting conditions. Nevertheless, expression of a pre-spliced HAC1 copy in ire1Δ mutants restored Ftr1 localization and rescued the growth defects of the mutants. Both ire1Δ and hac1Δ mutants were avirulent in a mouse model of systemic candidiasis, indicating that an appropriate response to endoplasmic reticulum stress is important for the virulence of C. albicans. However, the specific requirement of Ire1 for the functionality of the high-affinity iron permease Ftr1, a well-established virulence factor, even in the absence of endoplasmic reticulum stress uncovers a novel Hac1-independent essential role of Ire1 in iron acquisition and virulence of C. albicans. |
| first_indexed | 2024-12-19T22:16:49Z |
| format | Article |
| id | doaj.art-2de2097e8b6d45b78049f183bad71f30 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-19T22:16:49Z |
| publishDate | 2022-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-2de2097e8b6d45b78049f183bad71f302022-12-21T20:03:45ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742022-02-01182e101028310.1371/journal.ppat.1010283The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicans.Bernardo Ramírez-ZavalaInes KrügerChristine DunkerIlse D JacobsenJoachim MorschhäuserProtein kinases play central roles in virtually all signaling pathways that enable organisms to adapt to their environment. Microbial pathogens must cope with severely restricted iron availability in mammalian hosts to invade and establish themselves within infected tissues. To uncover protein kinase signaling pathways that are involved in the adaptation of the pathogenic yeast Candida albicans to iron limitation, we generated a comprehensive protein kinase deletion mutant library of a wild-type strain. Screening of this library revealed that the protein kinase Ire1, which has a conserved role in the response of eukaryotic cells to endoplasmic reticulum stress, is essential for growth of C. albicans under iron-limiting conditions. Ire1 was not necessary for the activity of the transcription factor Sef1, which regulates the response of the fungus to iron limitation, and Sef1 target genes that are induced by iron depletion were normally upregulated in ire1Δ mutants. Instead, Ire1 was required for proper localization of the high-affinity iron permease Ftr1 to the cell membrane. Intriguingly, iron limitation did not cause increased endoplasmic reticulum stress, and the transcription factor Hac1, which is activated by Ire1-mediated removal of the non-canonical intron in the HAC1 mRNA, was dispensable for Ftr1 localization to the cell membrane and growth under iron-limiting conditions. Nevertheless, expression of a pre-spliced HAC1 copy in ire1Δ mutants restored Ftr1 localization and rescued the growth defects of the mutants. Both ire1Δ and hac1Δ mutants were avirulent in a mouse model of systemic candidiasis, indicating that an appropriate response to endoplasmic reticulum stress is important for the virulence of C. albicans. However, the specific requirement of Ire1 for the functionality of the high-affinity iron permease Ftr1, a well-established virulence factor, even in the absence of endoplasmic reticulum stress uncovers a novel Hac1-independent essential role of Ire1 in iron acquisition and virulence of C. albicans.https://doi.org/10.1371/journal.ppat.1010283 |
| spellingShingle | Bernardo Ramírez-Zavala Ines Krüger Christine Dunker Ilse D Jacobsen Joachim Morschhäuser The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicans. PLoS Pathogens |
| title | The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicans. |
| title_full | The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicans. |
| title_fullStr | The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicans. |
| title_full_unstemmed | The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicans. |
| title_short | The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicans. |
| title_sort | protein kinase ire1 has a hac1 independent essential role in iron uptake and virulence of candida albicans |
| url | https://doi.org/10.1371/journal.ppat.1010283 |
| work_keys_str_mv | AT bernardoramirezzavala theproteinkinaseire1hasahac1independentessentialroleinironuptakeandvirulenceofcandidaalbicans AT ineskruger theproteinkinaseire1hasahac1independentessentialroleinironuptakeandvirulenceofcandidaalbicans AT christinedunker theproteinkinaseire1hasahac1independentessentialroleinironuptakeandvirulenceofcandidaalbicans AT ilsedjacobsen theproteinkinaseire1hasahac1independentessentialroleinironuptakeandvirulenceofcandidaalbicans AT joachimmorschhauser theproteinkinaseire1hasahac1independentessentialroleinironuptakeandvirulenceofcandidaalbicans AT bernardoramirezzavala proteinkinaseire1hasahac1independentessentialroleinironuptakeandvirulenceofcandidaalbicans AT ineskruger proteinkinaseire1hasahac1independentessentialroleinironuptakeandvirulenceofcandidaalbicans AT christinedunker proteinkinaseire1hasahac1independentessentialroleinironuptakeandvirulenceofcandidaalbicans AT ilsedjacobsen proteinkinaseire1hasahac1independentessentialroleinironuptakeandvirulenceofcandidaalbicans AT joachimmorschhauser proteinkinaseire1hasahac1independentessentialroleinironuptakeandvirulenceofcandidaalbicans |