Calcium Binding Protein Ncs1 Is Calcineurin Regulated in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> and Essential for Cell Division and Virulence

ABSTRACT Intracellular calcium (Ca2+) is crucial for signal transduction in Cryptococcus neoformans, the major cause of fatal fungal meningitis. The calcineurin pathway is the only Ca2+-requiring signaling cascade implicated in cryptococcal stress adaptation and virulence, with Ca2+ binding mediated...

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Autores principales:	Eamim Daidrê Squizani, Júlia Catarina Vieira Reuwsaat, Sophie Lev, Heryk Motta, Julia Sperotto, Keren Kaufman-Francis, Desmarini Desmarini, Marilene Henning Vainstein, Charley Christian Staats, Julianne T. Djordjevic, Lívia Kmetzsch
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	calcium binding protein calcium sensor Cryptococcus neoformans calcium signaling Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/af512a2c632e48f29809129f84c64afb
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spelling	oai:doaj.org-article:af512a2c632e48f29809129f84c64afb2021-11-15T15:30:58ZCalcium Binding Protein Ncs1 Is Calcineurin Regulated in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> and Essential for Cell Division and Virulence10.1128/mSphere.00761-202379-5042https://doaj.org/article/af512a2c632e48f29809129f84c64afb2020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00761-20https://doaj.org/toc/2379-5042ABSTRACT Intracellular calcium (Ca2+) is crucial for signal transduction in Cryptococcus neoformans, the major cause of fatal fungal meningitis. The calcineurin pathway is the only Ca2+-requiring signaling cascade implicated in cryptococcal stress adaptation and virulence, with Ca2+ binding mediated by the EF-hand domains of the Ca2+ sensor protein calmodulin. In this study, we identified the cryptococcal ortholog of neuronal calcium sensor 1 (Ncs1) as a member of the EF-hand superfamily. We demonstrated that Ncs1 has a role in Ca2+ homeostasis under stress and nonstress conditions, as the ncs1Δ mutant is sensitive to a high Ca2+ concentration and has an elevated basal Ca2+ level. Furthermore, NCS1 expression is induced by Ca2+, with the Ncs1 protein adopting a punctate subcellular distribution. We also demonstrate that, in contrast to the case with Saccharomyces cerevisiae, NCS1 expression in C. neoformans is regulated by the calcineurin pathway via the transcription factor Crz1, as NCS1 expression is reduced by FK506 treatment and CRZ1 deletion. Moreover, the ncs1Δ mutant shares a high temperature and high Ca2+ sensitivity phenotype with the calcineurin and calmodulin mutants (cna1Δ and cam1Δ), and the NCS1 promoter contains two calcineurin/Crz1-dependent response elements (CDRE1). Ncs1 deficiency coincided with reduced growth, characterized by delayed bud emergence and aberrant cell division, and hypovirulence in a mouse infection model. In summary, our data show that Ncs1 has a significant role as a Ca2+ sensor in C. neoformans, working with calcineurin to regulate Ca2+ homeostasis and, consequently, promote fungal growth and virulence. IMPORTANCE Cryptococcus neoformans is the major cause of fungal meningitis in HIV-infected patients. Several studies have highlighted the important contributions of Ca2+ signaling and homeostasis to the virulence of C. neoformans. Here, we identify the cryptococcal ortholog of neuronal calcium sensor 1 (Ncs1) and demonstrate its role in Ca2+ homeostasis, bud emergence, cell cycle progression, and virulence. We also show that Ncs1 function is regulated by the calcineurin/Crz1 signaling cascade. Our work provides evidence of a link between Ca2+ homeostasis and cell cycle progression in C. neoformans.Eamim Daidrê SquizaniJúlia Catarina Vieira ReuwsaatSophie LevHeryk MottaJulia SperottoKeren Kaufman-FrancisDesmarini DesmariniMarilene Henning VainsteinCharley Christian StaatsJulianne T. DjordjevicLívia KmetzschAmerican Society for Microbiologyarticlecalcium binding proteincalcium sensorCryptococcus neoformanscalcium signalingMicrobiologyQR1-502ENmSphere, Vol 5, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	calcium binding protein calcium sensor Cryptococcus neoformans calcium signaling Microbiology QR1-502
spellingShingle	calcium binding protein calcium sensor Cryptococcus neoformans calcium signaling Microbiology QR1-502 Eamim Daidrê Squizani Júlia Catarina Vieira Reuwsaat Sophie Lev Heryk Motta Julia Sperotto Keren Kaufman-Francis Desmarini Desmarini Marilene Henning Vainstein Charley Christian Staats Julianne T. Djordjevic Lívia Kmetzsch Calcium Binding Protein Ncs1 Is Calcineurin Regulated in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> and Essential for Cell Division and Virulence
description	ABSTRACT Intracellular calcium (Ca2+) is crucial for signal transduction in Cryptococcus neoformans, the major cause of fatal fungal meningitis. The calcineurin pathway is the only Ca2+-requiring signaling cascade implicated in cryptococcal stress adaptation and virulence, with Ca2+ binding mediated by the EF-hand domains of the Ca2+ sensor protein calmodulin. In this study, we identified the cryptococcal ortholog of neuronal calcium sensor 1 (Ncs1) as a member of the EF-hand superfamily. We demonstrated that Ncs1 has a role in Ca2+ homeostasis under stress and nonstress conditions, as the ncs1Δ mutant is sensitive to a high Ca2+ concentration and has an elevated basal Ca2+ level. Furthermore, NCS1 expression is induced by Ca2+, with the Ncs1 protein adopting a punctate subcellular distribution. We also demonstrate that, in contrast to the case with Saccharomyces cerevisiae, NCS1 expression in C. neoformans is regulated by the calcineurin pathway via the transcription factor Crz1, as NCS1 expression is reduced by FK506 treatment and CRZ1 deletion. Moreover, the ncs1Δ mutant shares a high temperature and high Ca2+ sensitivity phenotype with the calcineurin and calmodulin mutants (cna1Δ and cam1Δ), and the NCS1 promoter contains two calcineurin/Crz1-dependent response elements (CDRE1). Ncs1 deficiency coincided with reduced growth, characterized by delayed bud emergence and aberrant cell division, and hypovirulence in a mouse infection model. In summary, our data show that Ncs1 has a significant role as a Ca2+ sensor in C. neoformans, working with calcineurin to regulate Ca2+ homeostasis and, consequently, promote fungal growth and virulence. IMPORTANCE Cryptococcus neoformans is the major cause of fungal meningitis in HIV-infected patients. Several studies have highlighted the important contributions of Ca2+ signaling and homeostasis to the virulence of C. neoformans. Here, we identify the cryptococcal ortholog of neuronal calcium sensor 1 (Ncs1) and demonstrate its role in Ca2+ homeostasis, bud emergence, cell cycle progression, and virulence. We also show that Ncs1 function is regulated by the calcineurin/Crz1 signaling cascade. Our work provides evidence of a link between Ca2+ homeostasis and cell cycle progression in C. neoformans.
format	article
author	Eamim Daidrê Squizani Júlia Catarina Vieira Reuwsaat Sophie Lev Heryk Motta Julia Sperotto Keren Kaufman-Francis Desmarini Desmarini Marilene Henning Vainstein Charley Christian Staats Julianne T. Djordjevic Lívia Kmetzsch
author_facet	Eamim Daidrê Squizani Júlia Catarina Vieira Reuwsaat Sophie Lev Heryk Motta Julia Sperotto Keren Kaufman-Francis Desmarini Desmarini Marilene Henning Vainstein Charley Christian Staats Julianne T. Djordjevic Lívia Kmetzsch
author_sort	Eamim Daidrê Squizani
title	Calcium Binding Protein Ncs1 Is Calcineurin Regulated in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> and Essential for Cell Division and Virulence
title_short	Calcium Binding Protein Ncs1 Is Calcineurin Regulated in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> and Essential for Cell Division and Virulence
title_full	Calcium Binding Protein Ncs1 Is Calcineurin Regulated in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> and Essential for Cell Division and Virulence
title_fullStr	Calcium Binding Protein Ncs1 Is Calcineurin Regulated in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> and Essential for Cell Division and Virulence
title_full_unstemmed	Calcium Binding Protein Ncs1 Is Calcineurin Regulated in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> and Essential for Cell Division and Virulence
title_sort	calcium binding protein ncs1 is calcineurin regulated in <named-content content-type="genus-species">cryptococcus neoformans</named-content> and essential for cell division and virulence
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/af512a2c632e48f29809129f84c64afb
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Calcium Binding Protein Ncs1 Is Calcineurin Regulated in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> and Essential for Cell Division and Virulence

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