Document Detail


Dsc orthologs are required for hypoxia adaptation, triazole drug responses, and fungal virulence in Aspergillus fumigatus.
MedLine Citation:
PMID:  23104569     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Hypoxia is an environmental stress encountered by Aspergillus fumigatus during invasive pulmonary aspergillosis (IPA). The ability of this mold to adapt to hypoxia is important for fungal virulence and genetically regulated in part by the sterol regulatory element binding protein (SREBP) SrbA. SrbA is required for fungal growth in the murine lung and to ultimately cause lethal disease in murine models of IPA. Here we identified and partially characterized four genes (dscA, dscB, dscC, and dscD, here referred to as dscA-D) with previously unknown functions in A. fumigatus that are orthologs of the Schizosaccharomyces pombe genes dsc1, dsc2, dsc3, and dsc4 (dsc1-4), which encode a Golgi E3 ligase complex critical for SREBP activation by proteolytic cleavage. A. fumigatus null dscA-D mutants displayed remarkable defects in hypoxic growth and increased susceptibility to triazole antifungal drugs. Consistent with the confirmed role of these genes in S. pombe, both ΔdscA and ΔdscC resulted in reduced cleavage of the SrbA precursor protein in A. fumigatus. Inoculation of corticosteroid immunosuppressed mice with ΔdscA and ΔdscC strains revealed that these genes are critical for A. fumigatus virulence. Reintroduction of SrbA amino acids 1 to 425, encompassing the N terminus DNA binding domain, into the ΔdscA strain was able to partially restore virulence, further supporting a mechanistic link between DscA and SrbA function. Thus, we have shown for the first time the importance of a previously uncharacterized group of genes in A. fumigatus that mediate hypoxia adaptation, fungal virulence, and triazole drug susceptibility and that are likely linked to regulation of SrbA function.
Authors:
Sven D Willger; E Jean Cornish; Dawoon Chung; Brittany A Fleming; Margaret M Lehmann; Srisombat Puttikamonkul; Robert A Cramer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-26
Journal Detail:
Title:  Eukaryotic cell     Volume:  11     ISSN:  1535-9786     ISO Abbreviation:  Eukaryotic Cell     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-29     Completed Date:  2013-05-09     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101130731     Medline TA:  Eukaryot Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1557-67     Citation Subset:  IM    
Affiliation:
Department of Immunology and Infectious Disease, Montana State University, Bozeman, Montana, USA.
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MeSH Terms
Descriptor/Qualifier:
Adaptation, Biological / genetics*
Anaerobiosis / genetics
Animals
Antifungal Agents / toxicity
Aspergillus fumigatus / genetics,  metabolism*,  pathogenicity
Drug Resistance, Fungal* / genetics
Female
Fungal Proteins / chemistry,  genetics*,  metabolism
Mice
Protein Precursors / chemistry,  genetics*,  metabolism
Protein Processing, Post-Translational
Protein Structure, Tertiary
Proteolysis
Triazoles / toxicity
Ubiquitin-Protein Ligases / chemistry,  genetics*,  metabolism
Virulence / genetics
Grant Support
ID/Acronym/Agency:
GM103500/GM/NIGMS NIH HHS; L40 AI084526/AI/NIAID NIH HHS; P20 RR020185/RR/NCRR NIH HHS; R01 AI081838/AI/NIAID NIH HHS; R01AI81838/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Antifungal Agents; 0/Fungal Proteins; 0/Protein Precursors; 0/Triazoles; EC 6.3.2.19/Ubiquitin-Protein Ligases
Comments/Corrections

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