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

PLoS Pathogens

Robert A. Cramer Jr.¹  Nora Grahl¹  Simon L. Newman²  Long Jason Lu²  Daryl L. Richie³  Kevin K. Fuller³  Laura Woollett³  David S. Askew³  Xizhi Feng³  Karthik Krishnan³  Judith C. Rhodes³  Margaret V. Powers-Fletcher³  Minlu Zhang⁴  William C. Nierman⁵  Lukas Hartl⁶  Vishukumar Aimanianda⁶  Jean-Paul Latgé⁶ 

[1] Department of Immunology & Infectious Diseases, Montana State University, Bozeman, Montana, United States of America;Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America;Department of Pathology & Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America;Division of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, United States of America;The J. Craig Venter Institute, Rockville, Maryland, United States of America;Unité des Aspergillus, Institut Pasteur, Paris, France

关键词: Aspergillus fumigatus;    Endoplasmic reticulum;    Gene expression;    Cell walls;    Fungi;    Polymerase chain reaction;    Transcription factors;    Homeostasis;   

DOI  :  10.1371/journal.ppat.1002330

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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, hacAi, or an ireA deletion mutant that was incapable of processing the hacA mRNA, ireAΔ10. 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.

【 授权许可】

CC BY