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Protein Kinase A Regulates Autophagy-Associated Proteins Impacting Growth and Virulence of Aspergillus fumigatus

Cellular recycling via autophagy-associated proteins is a key catabolic pathway critical to invasive fungal pathogen growth and virulence in the nutrient-limited host environment. Protein kinase A (PKA) is vital for the growth and virulence of numerous fungal pathogens. However, the underlying basis...

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Autores principales: Shwab, E. Keats, Juvvadi, Praveen R., Shaheen, Shareef K., Allen, John, Waitt, Greg, Soderblom, Erik J., Asfaw, Yohannes G., Moseley, M. Arthur, Steinbach, William J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029100/
https://www.ncbi.nlm.nih.gov/pubmed/35448585
http://dx.doi.org/10.3390/jof8040354
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author Shwab, E. Keats
Juvvadi, Praveen R.
Shaheen, Shareef K.
Allen, John
Waitt, Greg
Soderblom, Erik J.
Asfaw, Yohannes G.
Moseley, M. Arthur
Steinbach, William J.
author_facet Shwab, E. Keats
Juvvadi, Praveen R.
Shaheen, Shareef K.
Allen, John
Waitt, Greg
Soderblom, Erik J.
Asfaw, Yohannes G.
Moseley, M. Arthur
Steinbach, William J.
author_sort Shwab, E. Keats
collection PubMed
description Cellular recycling via autophagy-associated proteins is a key catabolic pathway critical to invasive fungal pathogen growth and virulence in the nutrient-limited host environment. Protein kinase A (PKA) is vital for the growth and virulence of numerous fungal pathogens. However, the underlying basis for its regulation of pathogenesis remains poorly understood in any species. Our Aspergillus fumigatus PKA-dependent whole proteome and phosphoproteome studies employing advanced mass spectroscopic approaches identified numerous previously undefined PKA-regulated proteins in catabolic pathways. Here, we demonstrate reciprocal inhibition of autophagy and PKA activity, and identify 16 autophagy-associated proteins as likely novel PKA-regulated effectors. We characterize the novel PKA-phosphoregulated sorting nexin Atg20, and demonstrate its importance for growth, cell wall stress response, and virulence of A. fumigatus in a murine infection model. Additionally, we identify physical and functional interaction of Atg20 with previously characterized sorting nexin Atg24. Furthermore, we demonstrate the importance of additional uncharacterized PKA-regulated putative autophagy-associated proteins to hyphal growth. Our data presented here indicate that PKA regulates the autophagy pathway much more extensively than previously known, including targeting of novel effector proteins with fungal-specific functions important for invasive disease.
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spelling pubmed-90291002022-04-23 Protein Kinase A Regulates Autophagy-Associated Proteins Impacting Growth and Virulence of Aspergillus fumigatus Shwab, E. Keats Juvvadi, Praveen R. Shaheen, Shareef K. Allen, John Waitt, Greg Soderblom, Erik J. Asfaw, Yohannes G. Moseley, M. Arthur Steinbach, William J. J Fungi (Basel) Article Cellular recycling via autophagy-associated proteins is a key catabolic pathway critical to invasive fungal pathogen growth and virulence in the nutrient-limited host environment. Protein kinase A (PKA) is vital for the growth and virulence of numerous fungal pathogens. However, the underlying basis for its regulation of pathogenesis remains poorly understood in any species. Our Aspergillus fumigatus PKA-dependent whole proteome and phosphoproteome studies employing advanced mass spectroscopic approaches identified numerous previously undefined PKA-regulated proteins in catabolic pathways. Here, we demonstrate reciprocal inhibition of autophagy and PKA activity, and identify 16 autophagy-associated proteins as likely novel PKA-regulated effectors. We characterize the novel PKA-phosphoregulated sorting nexin Atg20, and demonstrate its importance for growth, cell wall stress response, and virulence of A. fumigatus in a murine infection model. Additionally, we identify physical and functional interaction of Atg20 with previously characterized sorting nexin Atg24. Furthermore, we demonstrate the importance of additional uncharacterized PKA-regulated putative autophagy-associated proteins to hyphal growth. Our data presented here indicate that PKA regulates the autophagy pathway much more extensively than previously known, including targeting of novel effector proteins with fungal-specific functions important for invasive disease. MDPI 2022-03-30 /pmc/articles/PMC9029100/ /pubmed/35448585 http://dx.doi.org/10.3390/jof8040354 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Shwab, E. Keats
Juvvadi, Praveen R.
Shaheen, Shareef K.
Allen, John
Waitt, Greg
Soderblom, Erik J.
Asfaw, Yohannes G.
Moseley, M. Arthur
Steinbach, William J.
Protein Kinase A Regulates Autophagy-Associated Proteins Impacting Growth and Virulence of Aspergillus fumigatus
title Protein Kinase A Regulates Autophagy-Associated Proteins Impacting Growth and Virulence of Aspergillus fumigatus
title_full Protein Kinase A Regulates Autophagy-Associated Proteins Impacting Growth and Virulence of Aspergillus fumigatus
title_fullStr Protein Kinase A Regulates Autophagy-Associated Proteins Impacting Growth and Virulence of Aspergillus fumigatus
title_full_unstemmed Protein Kinase A Regulates Autophagy-Associated Proteins Impacting Growth and Virulence of Aspergillus fumigatus
title_short Protein Kinase A Regulates Autophagy-Associated Proteins Impacting Growth and Virulence of Aspergillus fumigatus
title_sort protein kinase a regulates autophagy-associated proteins impacting growth and virulence of aspergillus fumigatus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029100/
https://www.ncbi.nlm.nih.gov/pubmed/35448585
http://dx.doi.org/10.3390/jof8040354
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