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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 Δ ireA  mutant was avirulent in a mouse model of invasive aspergillosis, which contrasts the partial virulence of a Δ hacA  mutant, suggesting that IreA contributes to pathogenesis independently of HacA. In support of this conclusion, we found that the Δ ireA  mutant had more severe defects in the expression of multiple virulence-related traits relative to Δ hacA , 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 Δ ireA  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 .

HacA-Independent Functions of the ER Stress Sensor IreA Synergize with the Canonical UPR to Influence Virulence Traits in Aspergillus fumigatus