The protein kinase Ire1 impacts pathogenicity of Candida albicans by regulating homeostatic adaptation to endoplasmic reticulum stress

Shabnam Sircaik, Elvira Román, Priyanka Bapat, Keunsook K. Lee, David R. Andes, Neil A.R. Gow, Clarissa J. Nobile, Jesús Pla, Sneh Lata Panwar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)
17 Downloads (Pure)

Abstract

The unfolded protein response (UPR), crucial for the maintenance of endoplasmic reticulum (ER) homeostasis, is tied to the regulation of multiple cellular processes in pathogenic fungi. Here, we show that Candida albicans relies on an ER-resident protein, inositol-requiring enzyme 1 (Ire1) for sensing ER stress and activating the UPR. Compromised Ire1 function impacts cellular processes that are dependent on functional secretory homeostasis, as inferred from transcriptional profiling. Concordantly, an Ire1-mutant strain exhibits pleiotropic roles in ER stress response, antifungal tolerance, cell wall regulation and virulence-related traits. Hac1 is the downstream target of C. albicans Ire1 as it initiates the unconventional splicing of the 19 bp intron from HAC1 mRNA during tunicamycin-induced ER stress. Ire1 also activates the UPR in response to perturbations in cell wall integrity and cell membrane homeostasis in a manner that does not necessitate the splicing of HAC1 mRNA. Furthermore, the Ire1-mutant strain is severely defective in hyphal morphogenesis and biofilm formation as well as in establishing a successful infection in vivo. Together, these findings demonstrate that C. albicans Ire1 functions to regulate traits that are essential for virulence and suggest its importance in responding to multiple stresses, thus integrating various stress signals to maintain ER homeostasis.

Original languageEnglish
Article numbere13307
Number of pages19
JournalCellular Microbiology
Volume23
Issue number5
Early online date5 Jan 2021
DOIs
Publication statusPublished - 26 Jan 2021

Bibliographical note

Funding Information:
The authors thank Aaron P. Mitchell for providing strains and plasmids. The authors also thank all Panwar lab members for critical reading of the manuscript. Funding support from the Defence Research and Development Organization (LSRB‐358/SH&DD/2019) to S.L.P. is acknowledged. Additional funding from SERB, Department of Science and Technology, Government of India, under the umbrella project DST‐PURSE as well as Capacity Build‐up, UGC‐Resource Networking and UGC‐SAP awarded to Jawaharlal Nehru University is also acknowledged. S.S. acknowledges Junior and Senior Research Fellowships (UGC‐JRF/SRF) from the University Grant Commission (UGC) and SRF from the Indian Council for Medical Research (ICMR). Support from the Kamangar family in the form of an endowed chair to C.J.N., National Institutes of Health (NIH) grant R35GM124594 to C.J.N., PGC2018‐095047‐B‐I00 and InGEMICS‐CM S2017/BMD3691/Comunidad Autonoma de Madrid to J.P. and Wellcome as a Senior Investigator Award (101873/Z/13/Z), Collaborative Award (200208/A/15/Z) and Strategic Award (097377/Z11/Z) by the MRC Centre for Medical Mycology (MR/N006364/2) to N.A.R.G. is acknowledged.

Publisher Copyright:
© 2021 The Authors. Cellular Microbiology published by John Wiley & Sons Ltd

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

  • Immunology
  • Microbiology
  • Virology

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