Pleiotropic Effects of the P5-Type ATPase SpfA on Stress Response Networks Contribute to Virulence in the Pathogenic Mold Aspergillus fumigatus
| Autor: | Ginés Luengo-Gil, Shivani Reddy, David S. Askew, Laura A. Woollett, Vishukumar Aimanianda, Sarah Sze Wah Wong, José P. Guirao-Abad, Nikita Malev, Christina Grisham, Martin Weichert |
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| Přispěvatelé: | University of Cincinnati College of Medicine, Instituto Murciano de Investigación Biosanitaria Pascual Parrilla (IMIB), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by National Institutes of Health (NIH) grant R01 AI123158-01A1 to D.S.A. and a University of Cincinnati Department of Pathology and Laboratory Medicine pilot research grant to J.P.G.-A. |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
MESH: Signal Transduction Protein Folding ATPase UPR sterols Moths MESH: Virulence Endoplasmic Reticulum medicine.disease_cause Aspergillus fumigatus Gene Knockout Techniques Mice HacA MESH: Endoplasmic Reticulum Stress Protein targeting lipid metabolism MESH: Sequence Analysis RNA Homeostasis MESH: Animals [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology MESH: Gene Knockout Techniques Adenosine Triphosphatases Virulence biology MESH: Moths Spf1 Endoplasmic Reticulum Stress QR1-502 Cell biology MESH: Homeostasis Larva Female MESH: Fungal Proteins MESH: Aspergillus fumigatus ER stress Research Article Signal Transduction P5-type ATPases MESH: Protein Folding Microbiology Fungal Proteins redox balance MESH: Endoplasmic Reticulum Virology SERCA medicine MESH: Adenosine Triphosphatases Animals SpfA Secretion MESH: Mice Secretory pathway redox homeostasis Sequence Analysis RNA Endoplasmic reticulum fungi biology.organism_classification MESH: Male lipid homeostasis biology.protein Unfolded protein response cell wall MESH: Female MESH: Larva |
| Zdroj: | mBio, Vol 12, Iss 5 (2021) mBio mBio, 2021, 12 (5), pp.e0273521. ⟨10.1128/mBio.02735-21⟩ |
| ISSN: | 2150-7511 2161-2129 |
| Popis: | International audience; Aspergillus fumigatus is a human-pathogenic mold that extracts nutrients from the environment or from host tissues by secreting hydrolytic enzymes. The ability of A. fumigatus to adjust secretion levels in proportion to demand relies on the assistance of the unfolded protein response (UPR), an adaptive stress response pathway that regulates the unique protein-folding environment of the endoplasmic reticulum (ER). The P5-type ATPase Spf1 has recently been implicated in a novel mechanism of ER homeostasis that involves correcting errors in ER-membrane protein targeting. However, the contribution of this protein to the biology of A. fumigatus is unknown. Here, we employed a gene knockout and RNA sequencing strategy to determine the functional role of the A. fumigatus gene coding for the orthologous P5 ATPase SpfA. The data reveal that the spfA gene is induced by ER stress in a UPR-dependent manner. In the absence of spfA, the A. fumigatus transcriptome shifts toward a profile of altered redox and lipid balance, in addition to a signature of ER stress that includes srcA, encoding a second P-type ATPase in the ER. A ΔspfA deletion mutant showed increased sensitivity to ER stress, oxidative stress, and antifungal drugs that target the cell wall or plasma membrane. The combined loss of spfA and srcA exacerbated these phenotypes and attenuated virulence in two animal infection models. These findings demonstrate that the ER-resident ATPases SpfA and SrcA act jointly to support diverse adaptive functions of the ER that are necessary for fitness in the host environment.IMPORTANCE The fungal UPR is an adaptive signaling pathway in the ER that buffers fluctuations in ER stress but also serves as a virulence regulatory hub in species of pathogenic fungi that rely on secretory pathway homeostasis for pathogenicity. This study demonstrates that the gene encoding the ER-localized P5-type ATPase SpfA is a downstream target of the UPR in the pathogenic mold A. fumigatus and that it works together with a second ER-localized P-type ATPase, SrcA, to support ER homeostasis, oxidative stress resistance, susceptibility to antifungal drugs, and virulence of A. fumigatus. |
| Databáze: | OpenAIRE |
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