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HacA-Independent Functions of the ER Stress Sensor IreA Synergize with the Canonical UPR to Influence Virulence Traits in Aspergillus fumigatus
- Source :
- PLoS Pathogens, PLoS Pathogens, Public Library of Science, 2011, 7 (10), pp.e1002330. ⟨10.1371/journal.ppat.1002330⟩, PLoS Pathogens, 2011, 7 (10), pp.e1002330. ⟨10.1371/journal.ppat.1002330⟩, PLoS Pathogens, Vol 7, Iss 10, p e1002330 (2011)
- Publication Year :
- 2011
- Publisher :
- HAL CCSD, 2011.
-
Abstract
- Endoplasmic reticulum (ER) stress is a condition in which the protein folding capacity of the ER becomes overwhelmed by an increased demand for secretion or by exposure to compounds that disrupt ER homeostasis. In yeast and other fungi, the accumulation of unfolded proteins is detected by the ER-transmembrane sensor IreA/Ire1, which responds by cleaving an intron from the downstream cytoplasmic mRNA HacA/Hac1, allowing for the translation of a transcription factor that coordinates a series of adaptive responses that are collectively known as the unfolded protein response (UPR). Here, we examined the contribution of IreA to growth and virulence in the human fungal pathogen Aspergillus fumigatus. Gene expression profiling revealed that A. fumigatus IreA signals predominantly through the canonical IreA-HacA pathway under conditions of severe ER stress. However, in the absence of ER stress IreA controls dual signaling circuits that are both HacA-dependent and HacA-independent. We found that a ΔireA mutant was avirulent in a mouse model of invasive aspergillosis, which contrasts the partial virulence of a ΔhacA mutant, suggesting that IreA contributes to pathogenesis independently of HacA. In support of this conclusion, we found that the ΔireA mutant had more severe defects in the expression of multiple virulence-related traits relative to ΔhacA, including reduced thermotolerance, decreased nutritional versatility, impaired growth under hypoxia, altered cell wall and membrane composition, and increased susceptibility to azole antifungals. In addition, full or partial virulence could be restored to the ΔireA mutant by complementation with either the induced form of the hacA mRNA, hacA i, or an ireA deletion mutant that was incapable of processing the hacA mRNA, ireA Δ10. Together, these findings demonstrate that IreA has both HacA-dependent and HacA-independent functions that contribute to the expression of traits that are essential for virulence in A. fumigatus.<br />Author Summary Aspergillus fumigatus is the predominant mold pathogen of humans, responsible for life-threatening infections in patients with depressed immunity. The fungus is highly adapted for secretion, a feature that it uses to extract nutrients from the host environment. High rates of protein secretion can overwhelm the protein folding capacity of the endoplasmic reticulum (ER). The resulting ER stress is alleviated by the unfolded protein response (UPR), a signaling pathway that is triggered by the ER-membrane sensor IreA and executed by the downstream transcription factor HacA. This paper uncovers a novel role for IreA in the expression of multiple adaptive traits that allow the fungus to cope with stress conditions that are encountered during infection. Gene expression profiling of ΔireA and ΔhacA mutants revealed that IreA signals predominantly through the canonical IreA-HacA UPR pathway under extreme conditions of ER stress, but has unexpected HacA-dependent and HacA-independent functions even in the absence of ER stress. These findings establish IreA as an important regulator of A. fumigatus pathogenicity and suggest that therapeutic targeting of the dual functions of this protein could be an effective antifungal strategy.
- Subjects :
- Fungal Physiology
Mutant
Pathogenesis
Endoplasmic Reticulum
Aspergillus fumigatus
Mice
Molecular Cell Biology
Gene expression
Biology (General)
Lung
[SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology
Cellular Stress Responses
Regulation of gene expression
Genetics
0303 health sciences
Fungal protein
Membrane Glycoproteins
Virulence
Iron-Regulatory Proteins
Cell biology
Female
Research Article
QH301-705.5
Genes, Fungal
Immunology
Mycology
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Biology
Microbiology
Cell Growth
Fungal Proteins
03 medical and health sciences
Virology
Animals, Outbred Strains
Animals
Humans
Secretion
RNA, Messenger
Molecular Biology
030304 developmental biology
030306 microbiology
Gene Expression Profiling
Fungi
RC581-607
biology.organism_classification
Repressor Proteins
Disease Models, Animal
Gene Expression Regulation
Mutation
Unfolded Protein Response
Unfolded protein response
Parasitology
Immunologic diseases. Allergy
Subjects
Details
- Language :
- English
- ISSN :
- 15537366 and 15537374
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens, PLoS Pathogens, Public Library of Science, 2011, 7 (10), pp.e1002330. ⟨10.1371/journal.ppat.1002330⟩, PLoS Pathogens, 2011, 7 (10), pp.e1002330. ⟨10.1371/journal.ppat.1002330⟩, PLoS Pathogens, Vol 7, Iss 10, p e1002330 (2011)
- Accession number :
- edsair.doi.dedup.....a2a769a710ece3a7b4528792668c47f5