Cross Talk between the Cell Wall Integrity and Cyclic AMP/Protein Kinase A Pathways in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>

ABSTRACT Cryptococcus neoformans is a fungal pathogen of immunocompromised people that causes fatal meningitis. The fungal cell wall is essential to viability and pathogenesis of C. neoformans, and biosynthesis and repair of the wall is primarily controlled by the cell wall integrity (CWI) signaling...

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Autores principales:	Maureen J. Donlin, Rajendra Upadhya, Kimberly J. Gerik, Woei Lam, Laura G. VanArendonk, Charles A. Specht, Neil K. Sharma, Jennifer K. Lodge
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/74664092951f4412ab343bbff9e8ce97
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spelling	oai:doaj.org-article:74664092951f4412ab343bbff9e8ce972021-11-15T15:47:22ZCross Talk between the Cell Wall Integrity and Cyclic AMP/Protein Kinase A Pathways in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>10.1128/mBio.01573-142150-7511https://doaj.org/article/74664092951f4412ab343bbff9e8ce972014-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01573-14https://doaj.org/toc/2150-7511ABSTRACT Cryptococcus neoformans is a fungal pathogen of immunocompromised people that causes fatal meningitis. The fungal cell wall is essential to viability and pathogenesis of C. neoformans, and biosynthesis and repair of the wall is primarily controlled by the cell wall integrity (CWI) signaling pathway. Previous work has shown that deletion of genes encoding the four major kinases in the CWI signaling pathway, namely, PKC1, BCK1, MKK2, and MPK1 results in severe cell wall phenotypes, sensitivity to a variety of cell wall stressors, and for Mpk1, reduced virulence in a mouse model. Here, we examined the global transcriptional responses to gene deletions of BCK1, MKK2, and MPK1 compared to wild-type cells. We found that over 1,000 genes were differentially expressed in one or more of the deletion strains, with 115 genes differentially expressed in all three strains, many of which have been identified as genes regulated by the cyclic AMP (cAMP)/protein kinase A (PKA) pathway. Biochemical measurements of cAMP levels in the kinase deletion strains revealed significantly less cAMP in all of the deletion strains compared to the wild-type strain. The deletion strains also produced significantly smaller capsules than the wild-type KN99 strain did under capsule-inducing conditions, although the levels of capsule they shed were similar to those shed by the wild type. Finally, addition of exogenous cAMP led to reduced sensitivity to cell wall stress and restored surface capsule to levels near those of wild type. Thus, we have direct evidence of cross talk between the CWI and cAMP/PKA pathways that may have important implications for regulation of cell wall and capsule homeostasis. IMPORTANCE Cryptococcus neoformans is a fungal pathogen of immunocompromised people that causes fatal meningitis. The fungal cell wall is essential to viability and pathogenesis of C. neoformans, and biosynthesis and repair of the wall are primarily controlled by the cell wall integrity (CWI) signaling pathway. In this study, we demonstrate that deletion of any of three core kinases in the CWI pathway impacts not only the cell wall but also the amount of surface capsule. Deletion of any of the kinases results in significantly reduced cellular cyclic AMP (cAMP) levels, and addition of exogenous cAMP rescues the capsule defect and some cell wall defects, supporting a direct role for the CWI pathway in regulation of capsule in conjunction with the cAMP/protein kinase A pathway.Maureen J. DonlinRajendra UpadhyaKimberly J. GerikWoei LamLaura G. VanArendonkCharles A. SpechtNeil K. SharmaJennifer K. LodgeAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 4 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Maureen J. Donlin Rajendra Upadhya Kimberly J. Gerik Woei Lam Laura G. VanArendonk Charles A. Specht Neil K. Sharma Jennifer K. Lodge Cross Talk between the Cell Wall Integrity and Cyclic AMP/Protein Kinase A Pathways in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
description	ABSTRACT Cryptococcus neoformans is a fungal pathogen of immunocompromised people that causes fatal meningitis. The fungal cell wall is essential to viability and pathogenesis of C. neoformans, and biosynthesis and repair of the wall is primarily controlled by the cell wall integrity (CWI) signaling pathway. Previous work has shown that deletion of genes encoding the four major kinases in the CWI signaling pathway, namely, PKC1, BCK1, MKK2, and MPK1 results in severe cell wall phenotypes, sensitivity to a variety of cell wall stressors, and for Mpk1, reduced virulence in a mouse model. Here, we examined the global transcriptional responses to gene deletions of BCK1, MKK2, and MPK1 compared to wild-type cells. We found that over 1,000 genes were differentially expressed in one or more of the deletion strains, with 115 genes differentially expressed in all three strains, many of which have been identified as genes regulated by the cyclic AMP (cAMP)/protein kinase A (PKA) pathway. Biochemical measurements of cAMP levels in the kinase deletion strains revealed significantly less cAMP in all of the deletion strains compared to the wild-type strain. The deletion strains also produced significantly smaller capsules than the wild-type KN99 strain did under capsule-inducing conditions, although the levels of capsule they shed were similar to those shed by the wild type. Finally, addition of exogenous cAMP led to reduced sensitivity to cell wall stress and restored surface capsule to levels near those of wild type. Thus, we have direct evidence of cross talk between the CWI and cAMP/PKA pathways that may have important implications for regulation of cell wall and capsule homeostasis. IMPORTANCE Cryptococcus neoformans is a fungal pathogen of immunocompromised people that causes fatal meningitis. The fungal cell wall is essential to viability and pathogenesis of C. neoformans, and biosynthesis and repair of the wall are primarily controlled by the cell wall integrity (CWI) signaling pathway. In this study, we demonstrate that deletion of any of three core kinases in the CWI pathway impacts not only the cell wall but also the amount of surface capsule. Deletion of any of the kinases results in significantly reduced cellular cyclic AMP (cAMP) levels, and addition of exogenous cAMP rescues the capsule defect and some cell wall defects, supporting a direct role for the CWI pathway in regulation of capsule in conjunction with the cAMP/protein kinase A pathway.
format	article
author	Maureen J. Donlin Rajendra Upadhya Kimberly J. Gerik Woei Lam Laura G. VanArendonk Charles A. Specht Neil K. Sharma Jennifer K. Lodge
author_facet	Maureen J. Donlin Rajendra Upadhya Kimberly J. Gerik Woei Lam Laura G. VanArendonk Charles A. Specht Neil K. Sharma Jennifer K. Lodge
author_sort	Maureen J. Donlin
title	Cross Talk between the Cell Wall Integrity and Cyclic AMP/Protein Kinase A Pathways in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_short	Cross Talk between the Cell Wall Integrity and Cyclic AMP/Protein Kinase A Pathways in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_full	Cross Talk between the Cell Wall Integrity and Cyclic AMP/Protein Kinase A Pathways in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_fullStr	Cross Talk between the Cell Wall Integrity and Cyclic AMP/Protein Kinase A Pathways in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_full_unstemmed	Cross Talk between the Cell Wall Integrity and Cyclic AMP/Protein Kinase A Pathways in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_sort	cross talk between the cell wall integrity and cyclic amp/protein kinase a pathways in <named-content content-type="genus-species">cryptococcus neoformans</named-content>
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/74664092951f4412ab343bbff9e8ce97
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Cross Talk between the Cell Wall Integrity and Cyclic AMP/Protein Kinase A Pathways in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>

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