Abstract
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.
Highlights
Microorganisms must be able to obtain all nutrients that are required for growth from their surroundings
We systematically investigated the role of protein kinases, which are part of virtually all signal transduction pathways that regulate cellular responses to environmental changes, in the adaptation of C. albicans to the severely iron-restricted conditions encountered in blood and internal organs
We found that the protein kinase Ire1 is essential for the ability of C. albicans to grow under iron-depleted conditions, it is not required for the upregulation of genes that are induced in response to iron limitation
Summary
Microorganisms must be able to obtain all nutrients that are required for growth from their surroundings. Efficient iron uptake systems are required for a successful establishment and growth of microorganisms in such environments [2]. Current evidence indicates that iron is obtainable for commensal growth of C. albicans in at least some parts of the gastrointestinal tract, such that its uptake has to be limited to avoid toxic effects of excess iron within the cells [3]. Virtually no free iron is available in blood and internal organs, and C. albicans depends on efficient iron acquisition mechanisms to be able to cause a systemic infection [4]. C. albicans can utilize heme from hemoglobin as an iron source via a specific transport system, and mutants lacking components of this system display reduced virulence in a mouse model of systemic candidiasis [10]. C. albicans can extract iron from other host proteins, such as ferritin and transferrin, using specific surface proteins and the reductive iron assimilation pathway, and it can utilize iron-containing siderophores produced by other microorganisms [11,12,13]
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