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Modulation of azole sensitivity and filamentation by GPI15, encoding a subunit of the first GPI biosynthetic enzyme, in Candida albicans

Glycosylphosphatidylinositol (GPI)-anchored proteins are important for virulence of many pathogenic organisms including the human fungal pathogen, Candida albicans. GPI biosynthesis is initiated by a multi-subunit enzyme, GPI-N-acetylglucosaminyltransferase (GPI-GnT). We showed previously that two G...

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Autores principales: Jain, Priyanka, Garai, Pramita, Sethi, Subhash Chandra, Naqvi, Nilofer, Yadav, Bhawna, Kumar, Pravin, Singh, Sneh Lata, Yadav, Usha, Bhatnagar, Shilpi, Rahul, Puri, Niti, Muthuswami, Rohini, Komath, Sneha Sudha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559964/
https://www.ncbi.nlm.nih.gov/pubmed/31186458
http://dx.doi.org/10.1038/s41598-019-44919-4
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author Jain, Priyanka
Garai, Pramita
Sethi, Subhash Chandra
Naqvi, Nilofer
Yadav, Bhawna
Kumar, Pravin
Singh, Sneh Lata
Yadav, Usha
Bhatnagar, Shilpi
Rahul
Puri, Niti
Muthuswami, Rohini
Komath, Sneha Sudha
author_facet Jain, Priyanka
Garai, Pramita
Sethi, Subhash Chandra
Naqvi, Nilofer
Yadav, Bhawna
Kumar, Pravin
Singh, Sneh Lata
Yadav, Usha
Bhatnagar, Shilpi
Rahul
Puri, Niti
Muthuswami, Rohini
Komath, Sneha Sudha
author_sort Jain, Priyanka
collection PubMed
description Glycosylphosphatidylinositol (GPI)-anchored proteins are important for virulence of many pathogenic organisms including the human fungal pathogen, Candida albicans. GPI biosynthesis is initiated by a multi-subunit enzyme, GPI-N-acetylglucosaminyltransferase (GPI-GnT). We showed previously that two GPI-GnT subunits, encoded by CaGPI2 and CaGPI19, are mutually repressive. CaGPI19 also co-regulates CaERG11, the target of azoles while CaGPI2 controls Ras signaling and hyphal morphogenesis. Here, we investigated the role of a third subunit. We show that CaGpi15 is functionally homologous to Saccharomyces cerevisiae Gpi15. CaGPI15 is a master activator of CaGPI2 and CaGPI19. Hence, CaGPI15 mutants are azole-sensitive and hypofilamentous. Altering CaGPI19 or CaGPI2 expression in CaGPI15 mutant can elicit alterations in azole sensitivity via CaERG11 expression or hyphal morphogenesis, respectively. Thus, CaGPI2 and CaGPI19 function downstream of CaGPI15. One mode of regulation is via H3 acetylation of the respective GPI-GnT gene promoters by Rtt109. Azole sensitivity of GPI-GnT mutants is also due to decreased H3 acetylation at the CaERG11 promoter by Rtt109. Using double heterozygous mutants, we also show that CaGPI2 and CaGPI19 can independently activate CaGPI15. CaGPI15 mutant is more susceptible to killing by macrophages and epithelial cells and has reduced ability to damage either of these cell lines relative to the wild type strain, suggesting that it is attenuated in virulence.
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spelling pubmed-65599642019-06-19 Modulation of azole sensitivity and filamentation by GPI15, encoding a subunit of the first GPI biosynthetic enzyme, in Candida albicans Jain, Priyanka Garai, Pramita Sethi, Subhash Chandra Naqvi, Nilofer Yadav, Bhawna Kumar, Pravin Singh, Sneh Lata Yadav, Usha Bhatnagar, Shilpi Rahul Puri, Niti Muthuswami, Rohini Komath, Sneha Sudha Sci Rep Article Glycosylphosphatidylinositol (GPI)-anchored proteins are important for virulence of many pathogenic organisms including the human fungal pathogen, Candida albicans. GPI biosynthesis is initiated by a multi-subunit enzyme, GPI-N-acetylglucosaminyltransferase (GPI-GnT). We showed previously that two GPI-GnT subunits, encoded by CaGPI2 and CaGPI19, are mutually repressive. CaGPI19 also co-regulates CaERG11, the target of azoles while CaGPI2 controls Ras signaling and hyphal morphogenesis. Here, we investigated the role of a third subunit. We show that CaGpi15 is functionally homologous to Saccharomyces cerevisiae Gpi15. CaGPI15 is a master activator of CaGPI2 and CaGPI19. Hence, CaGPI15 mutants are azole-sensitive and hypofilamentous. Altering CaGPI19 or CaGPI2 expression in CaGPI15 mutant can elicit alterations in azole sensitivity via CaERG11 expression or hyphal morphogenesis, respectively. Thus, CaGPI2 and CaGPI19 function downstream of CaGPI15. One mode of regulation is via H3 acetylation of the respective GPI-GnT gene promoters by Rtt109. Azole sensitivity of GPI-GnT mutants is also due to decreased H3 acetylation at the CaERG11 promoter by Rtt109. Using double heterozygous mutants, we also show that CaGPI2 and CaGPI19 can independently activate CaGPI15. CaGPI15 mutant is more susceptible to killing by macrophages and epithelial cells and has reduced ability to damage either of these cell lines relative to the wild type strain, suggesting that it is attenuated in virulence. Nature Publishing Group UK 2019-06-11 /pmc/articles/PMC6559964/ /pubmed/31186458 http://dx.doi.org/10.1038/s41598-019-44919-4 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Jain, Priyanka
Garai, Pramita
Sethi, Subhash Chandra
Naqvi, Nilofer
Yadav, Bhawna
Kumar, Pravin
Singh, Sneh Lata
Yadav, Usha
Bhatnagar, Shilpi
Rahul
Puri, Niti
Muthuswami, Rohini
Komath, Sneha Sudha
Modulation of azole sensitivity and filamentation by GPI15, encoding a subunit of the first GPI biosynthetic enzyme, in Candida albicans
title Modulation of azole sensitivity and filamentation by GPI15, encoding a subunit of the first GPI biosynthetic enzyme, in Candida albicans
title_full Modulation of azole sensitivity and filamentation by GPI15, encoding a subunit of the first GPI biosynthetic enzyme, in Candida albicans
title_fullStr Modulation of azole sensitivity and filamentation by GPI15, encoding a subunit of the first GPI biosynthetic enzyme, in Candida albicans
title_full_unstemmed Modulation of azole sensitivity and filamentation by GPI15, encoding a subunit of the first GPI biosynthetic enzyme, in Candida albicans
title_short Modulation of azole sensitivity and filamentation by GPI15, encoding a subunit of the first GPI biosynthetic enzyme, in Candida albicans
title_sort modulation of azole sensitivity and filamentation by gpi15, encoding a subunit of the first gpi biosynthetic enzyme, in candida albicans
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559964/
https://www.ncbi.nlm.nih.gov/pubmed/31186458
http://dx.doi.org/10.1038/s41598-019-44919-4
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