Cdk8 and Ssn801 Regulate Oxidative Stress Resistance and Virulence in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>

ABSTRACT Cryptococcus neoformans kills 200,000 people worldwide each year. After inhalation, this environmental yeast proliferates either extracellularly or within host macrophages. Under conditions of immunocompromise, cryptococci disseminate from the lungs to the brain, causing a deadly meningoenc...

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Autores principales:	Andrew L. Chang, Yiming Kang, Tamara L. Doering
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Cdk8 Cryptococcus neoformans Mediator complex Ssn801 mitochondria Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/879ad443fab1444ea0a1a52cd0132968
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spelling	oai:doaj.org-article:879ad443fab1444ea0a1a52cd01329682021-11-15T15:55:14ZCdk8 and Ssn801 Regulate Oxidative Stress Resistance and Virulence in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>10.1128/mBio.02818-182150-7511https://doaj.org/article/879ad443fab1444ea0a1a52cd01329682019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02818-18https://doaj.org/toc/2150-7511ABSTRACT Cryptococcus neoformans kills 200,000 people worldwide each year. After inhalation, this environmental yeast proliferates either extracellularly or within host macrophages. Under conditions of immunocompromise, cryptococci disseminate from the lungs to the brain, causing a deadly meningoencephalitis that is difficult and expensive to treat. Cryptococcal adaptation to the harsh lung environment is a critical first step in its pathogenesis, and consequently a compelling topic of study. This adaptation is mediated by a complex transcriptional program that integrates cellular responses to environmental stimuli. Although several key regulators in this process have been examined, one that remains understudied in C. neoformans is the Mediator complex. In other organisms, this complex promotes transcription of specific genes by increasing assembly of the RNA polymerase II preinitiation complex. We focused on the Kinase Module of Mediator, which consists of cyclin C (Ssn801), cyclin-dependent kinase 8 (Cdk8), Med12, and Med13. This module provides important inhibitory control of Mediator complex assembly and activity. Using transcriptomics, we discovered that Cdk8 and Ssn801 together regulate cryptococcal functions such as the ability to grow on acetate and the response to oxidative stress, both of which were experimentally validated. Deletion of CDK8 yielded altered mitochondrial morphology and the dysregulation of genes involved in oxidation-reduction processes. This strain exhibited increased susceptibility to oxidative stress, resulting in an inability of mutant cells to proliferate within phagocytes, decreased lung burdens, and attenuated virulence in vivo. These findings increase our understanding of cryptococcal adaptation to the host environment and its regulation of oxidative stress resistance and virulence. IMPORTANCE Cryptococcus neoformans is a fungal pathogen that primarily affects severely immunocompromised patients, resulting in 200,000 deaths every year. This yeast occurs in the environment and can establish disease upon inhalation into the lungs of a mammalian host. In this harsh environment it must survive engulfment by host phagocytes, including the oxidative stresses it experiences inside them. To adapt to these challenging conditions, C. neoformans deploys a variety of regulatory proteins to alter gene expression levels and enhance its ability to survive. We have elucidated the role of a protein complex that regulates the cryptococcal response to oxidative stress, survival within phagocytes, and ability to cause disease. These findings are important because they advance our understanding of cryptococcal disease, which we hope will help in the efforts to control this devastating infection.Andrew L. ChangYiming KangTamara L. DoeringAmerican Society for MicrobiologyarticleCdk8Cryptococcus neoformansMediator complexSsn801mitochondriaMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cdk8 Cryptococcus neoformans Mediator complex Ssn801 mitochondria Microbiology QR1-502
spellingShingle	Cdk8 Cryptococcus neoformans Mediator complex Ssn801 mitochondria Microbiology QR1-502 Andrew L. Chang Yiming Kang Tamara L. Doering Cdk8 and Ssn801 Regulate Oxidative Stress Resistance and Virulence in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
description	ABSTRACT Cryptococcus neoformans kills 200,000 people worldwide each year. After inhalation, this environmental yeast proliferates either extracellularly or within host macrophages. Under conditions of immunocompromise, cryptococci disseminate from the lungs to the brain, causing a deadly meningoencephalitis that is difficult and expensive to treat. Cryptococcal adaptation to the harsh lung environment is a critical first step in its pathogenesis, and consequently a compelling topic of study. This adaptation is mediated by a complex transcriptional program that integrates cellular responses to environmental stimuli. Although several key regulators in this process have been examined, one that remains understudied in C. neoformans is the Mediator complex. In other organisms, this complex promotes transcription of specific genes by increasing assembly of the RNA polymerase II preinitiation complex. We focused on the Kinase Module of Mediator, which consists of cyclin C (Ssn801), cyclin-dependent kinase 8 (Cdk8), Med12, and Med13. This module provides important inhibitory control of Mediator complex assembly and activity. Using transcriptomics, we discovered that Cdk8 and Ssn801 together regulate cryptococcal functions such as the ability to grow on acetate and the response to oxidative stress, both of which were experimentally validated. Deletion of CDK8 yielded altered mitochondrial morphology and the dysregulation of genes involved in oxidation-reduction processes. This strain exhibited increased susceptibility to oxidative stress, resulting in an inability of mutant cells to proliferate within phagocytes, decreased lung burdens, and attenuated virulence in vivo. These findings increase our understanding of cryptococcal adaptation to the host environment and its regulation of oxidative stress resistance and virulence. IMPORTANCE Cryptococcus neoformans is a fungal pathogen that primarily affects severely immunocompromised patients, resulting in 200,000 deaths every year. This yeast occurs in the environment and can establish disease upon inhalation into the lungs of a mammalian host. In this harsh environment it must survive engulfment by host phagocytes, including the oxidative stresses it experiences inside them. To adapt to these challenging conditions, C. neoformans deploys a variety of regulatory proteins to alter gene expression levels and enhance its ability to survive. We have elucidated the role of a protein complex that regulates the cryptococcal response to oxidative stress, survival within phagocytes, and ability to cause disease. These findings are important because they advance our understanding of cryptococcal disease, which we hope will help in the efforts to control this devastating infection.
format	article
author	Andrew L. Chang Yiming Kang Tamara L. Doering
author_facet	Andrew L. Chang Yiming Kang Tamara L. Doering
author_sort	Andrew L. Chang
title	Cdk8 and Ssn801 Regulate Oxidative Stress Resistance and Virulence in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_short	Cdk8 and Ssn801 Regulate Oxidative Stress Resistance and Virulence in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_full	Cdk8 and Ssn801 Regulate Oxidative Stress Resistance and Virulence in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_fullStr	Cdk8 and Ssn801 Regulate Oxidative Stress Resistance and Virulence in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_full_unstemmed	Cdk8 and Ssn801 Regulate Oxidative Stress Resistance and Virulence in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_sort	cdk8 and ssn801 regulate oxidative stress resistance and virulence in <named-content content-type="genus-species">cryptococcus neoformans</named-content>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/879ad443fab1444ea0a1a52cd0132968
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Cdk8 and Ssn801 Regulate Oxidative Stress Resistance and Virulence in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>

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