The Endoplasmic Reticulum (ER) Stress Sensor Ire1/IreA Links ER Homeostasis With Multiple Virulence-related Traits In The Mold Pathogen Aspergillus fumigatus

X. Feng, K. Krishnan, D. R. Richie, D. S. Askew

Author address: 

Univ. of Cincinnati, Cincinnati, OH.

Abstract: 

Background:

The unfolded protein response (UPR) is a stress response pathway that maintains endoplasmic reticulum (ER) homeostasis by increasing the folding capacity of the ER in proportion to the demand for secretion. In yeast, the UPR is triggered by Ire1, a bifunctional kinase/endoribonuclease located in the ER membrane. Activation of the Ire1 endoribonuclease domain removes an intron from the cytoplasmic mRNA HAC1, creating a frame-shift that directs the translation of the master transcriptional regulator of the UPR, Hac1p. Despite advances in understanding Ire1 function in yeast, nothing is known about its contribution to the biology of Aspergillus fumigatus, the predominant mold pathogen of humans. The purpose of this study was to determine the role of IreA (the ortholog of yeast Ire1) to growth and virulence of A. fumigatus.

Methods:

IreA-deficient mutants were constructed by targeted deletion of the ireA gene (916;ireA) or by deletion of the active site in the endoribonuclease domain (ireA916;10).

Results:

Neither the 916;ireA mutant, nor the ireA916;10 mutant were able to process the hacA mRNA in response to ER stress. The 916;ireA mutant was avirulent and was hypersensitive to antifungal drugs that target the cell wall and membrane. The 916;ireA mutant displayed a reduced capacity for protease secretion and was growth impaired under hypoxic conditions. Each of these phenotypes was strikingly more severe in the 916;ireA mutant relative to 916;hacA.

Conclusion:

These findings demonstrate that the IreA endoribonuclease is required for hacA processing in A. fumigatus and provide unexpected evidence that IreA has unique HacA-independent functions that are relevant to virulence.

2011

abstract No: 

1190

Full conference title: 

111th General Meeting American Society for Microbiology
    • ASM 111th (2011)