HacA-independent functions of the ER stress sensor IreA synergize with the canonical UPR to influence virulence traits in Aspergillus fumigatus.
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.
Department of Pathology & Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
Xizhi
X
Feng
Karthik
K
Krishnan
Daryl L
DL
Richie
Vishukumar
V
Aimanianda
Lukas
L
Hartl
Nora
N
Grahl
Margaret V
MV
Powers-Fletcher
Minlu
M
Zhang
Kevin K
KK
Fuller
William C
WC
Nierman
Long Jason
LJ
Lu
Jean-Paul
JP
Latgé
Laura
L
Woollett
Simon L
SL
Newman
Robert A
RA
Cramer
Judith C
JC
Rhodes
David S
DS
Askew
D000818:Animals; D021461:Animals, Outbred Strains; D001232:Aspergillus fumigatus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005800:Genes, Fungal; D006801:Humans; D035925:Iron-Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008562:Membrane Glycoproteins; D051379:Mice; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000502:physiology*; D014774:Virulence / Q000235:genetics
D005656:Fungal Proteins; D035925:Iron-Regulatory Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D012097:Repressor Proteins