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.
Highlights
One third of the eukaryotic proteome is dedicated to secreted and membrane proteins, making the secretory pathway one of the most active biosynthetic processes in the cell
The resulting endoplasmic reticulum (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
Gene expression profiling of DireA and DhacA 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
Summary
One third of the eukaryotic proteome is dedicated to secreted and membrane proteins, making the secretory pathway one of the most active biosynthetic processes in the cell. A highly developed secretory system is an important virulence attribute of this organism because it provides a mechanism for the delivery of hydrolytic enzymes and membrane transporters into, and across, the membrane, which is essential for nutrient acquisition from the host [3] Many of these enzymes are responsible for damaging host tissues, which contributes to the high mortality rates associated with A. fumigatus infections [4]. Protein secretion begins in the endoplasmic reticulum (ER), an extensive membrane network that provides a segregated compartment for the precise folding, modification and export of extracellular and membrane proteins. The ability of this organelle to meet the demand for secretion is limited by the level of ERresident chaperones, foldases and other modifying enzymes that assist in protein folding [5]. Misfolded proteins can accumulate when the demand for secretion exceeds the protein
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