Relative Contributions of Prenylation and Postprenylation Processing in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Pathogenesis

ABSTRACT Prenyltransferase enzymes promote the membrane localization of their target proteins by directing the attachment of a hydrophobic lipid group at a conserved C-terminal CAAX motif. Subsequently, the prenylated protein is further modified by postprenylation processing enzymes that cleave the...

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Autores principales:	Shannon K. Esher, Kyla S. Ost, Lukasz Kozubowski, Dong-Hoon Yang, Min Su Kim, Yong-Sun Bahn, J. Andrew Alspaugh, Connie B. Nichols
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Cryptococcus neoformans farnesyltransferase fungal pathogen protein prenylation Ras-like GTPases Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/f4899708ff68499aa223282fe1165f78
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spelling	oai:doaj.org-article:f4899708ff68499aa223282fe1165f782021-11-15T15:21:22ZRelative Contributions of Prenylation and Postprenylation Processing in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Pathogenesis10.1128/mSphere.00084-152379-5042https://doaj.org/article/f4899708ff68499aa223282fe1165f782016-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00084-15https://doaj.org/toc/2379-5042ABSTRACT Prenyltransferase enzymes promote the membrane localization of their target proteins by directing the attachment of a hydrophobic lipid group at a conserved C-terminal CAAX motif. Subsequently, the prenylated protein is further modified by postprenylation processing enzymes that cleave the terminal 3 amino acids and carboxymethylate the prenylated cysteine residue. Many prenylated proteins, including Ras1 and Ras-like proteins, require this multistep membrane localization process in order to function properly. In the human fungal pathogen Cryptococcus neoformans, previous studies have demonstrated that two distinct forms of protein prenylation, farnesylation and geranylgeranylation, are both required for cellular adaptation to stress, as well as full virulence in animal infection models. Here, we establish that the C. neoformans RAM1 gene encoding the farnesyltransferase β-subunit, though not strictly essential for growth under permissive in vitro conditions, is absolutely required for cryptococcal pathogenesis. We also identify and characterize postprenylation protease and carboxyl methyltransferase enzymes in C. neoformans. In contrast to the prenyltransferases, deletion of the genes encoding the Rce1 protease and Ste14 carboxyl methyltransferase results in subtle defects in stress response and only partial reductions in virulence. These postprenylation modifications, as well as the prenylation events themselves, do play important roles in mating and hyphal transitions, likely due to their regulation of peptide pheromones and other proteins involved in development. IMPORTANCE Cryptococcus neoformans is an important human fungal pathogen that causes disease and death in immunocompromised individuals. The growth and morphogenesis of this fungus are controlled by conserved Ras-like GTPases, which are also important for its pathogenicity. Many of these proteins require proper subcellular localization for full function, and they are directed to cellular membranes through a posttranslational modification process known as prenylation. These studies investigate the roles of one of the prenylation enzymes, farnesyltransferase, as well as the postprenylation processing enzymes in C. neoformans. We demonstrate that the postprenylation processing steps are dispensable for the localization of certain substrate proteins. However, both protein farnesylation and the subsequent postprenylation processing steps are required for full pathogenesis of this fungus.Shannon K. EsherKyla S. OstLukasz KozubowskiDong-Hoon YangMin Su KimYong-Sun BahnJ. Andrew AlspaughConnie B. NicholsAmerican Society for MicrobiologyarticleCryptococcus neoformansfarnesyltransferasefungal pathogenprotein prenylationRas-like GTPasesMicrobiologyQR1-502ENmSphere, Vol 1, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cryptococcus neoformans farnesyltransferase fungal pathogen protein prenylation Ras-like GTPases Microbiology QR1-502
spellingShingle	Cryptococcus neoformans farnesyltransferase fungal pathogen protein prenylation Ras-like GTPases Microbiology QR1-502 Shannon K. Esher Kyla S. Ost Lukasz Kozubowski Dong-Hoon Yang Min Su Kim Yong-Sun Bahn J. Andrew Alspaugh Connie B. Nichols Relative Contributions of Prenylation and Postprenylation Processing in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Pathogenesis
description	ABSTRACT Prenyltransferase enzymes promote the membrane localization of their target proteins by directing the attachment of a hydrophobic lipid group at a conserved C-terminal CAAX motif. Subsequently, the prenylated protein is further modified by postprenylation processing enzymes that cleave the terminal 3 amino acids and carboxymethylate the prenylated cysteine residue. Many prenylated proteins, including Ras1 and Ras-like proteins, require this multistep membrane localization process in order to function properly. In the human fungal pathogen Cryptococcus neoformans, previous studies have demonstrated that two distinct forms of protein prenylation, farnesylation and geranylgeranylation, are both required for cellular adaptation to stress, as well as full virulence in animal infection models. Here, we establish that the C. neoformans RAM1 gene encoding the farnesyltransferase β-subunit, though not strictly essential for growth under permissive in vitro conditions, is absolutely required for cryptococcal pathogenesis. We also identify and characterize postprenylation protease and carboxyl methyltransferase enzymes in C. neoformans. In contrast to the prenyltransferases, deletion of the genes encoding the Rce1 protease and Ste14 carboxyl methyltransferase results in subtle defects in stress response and only partial reductions in virulence. These postprenylation modifications, as well as the prenylation events themselves, do play important roles in mating and hyphal transitions, likely due to their regulation of peptide pheromones and other proteins involved in development. IMPORTANCE Cryptococcus neoformans is an important human fungal pathogen that causes disease and death in immunocompromised individuals. The growth and morphogenesis of this fungus are controlled by conserved Ras-like GTPases, which are also important for its pathogenicity. Many of these proteins require proper subcellular localization for full function, and they are directed to cellular membranes through a posttranslational modification process known as prenylation. These studies investigate the roles of one of the prenylation enzymes, farnesyltransferase, as well as the postprenylation processing enzymes in C. neoformans. We demonstrate that the postprenylation processing steps are dispensable for the localization of certain substrate proteins. However, both protein farnesylation and the subsequent postprenylation processing steps are required for full pathogenesis of this fungus.
format	article
author	Shannon K. Esher Kyla S. Ost Lukasz Kozubowski Dong-Hoon Yang Min Su Kim Yong-Sun Bahn J. Andrew Alspaugh Connie B. Nichols
author_facet	Shannon K. Esher Kyla S. Ost Lukasz Kozubowski Dong-Hoon Yang Min Su Kim Yong-Sun Bahn J. Andrew Alspaugh Connie B. Nichols
author_sort	Shannon K. Esher
title	Relative Contributions of Prenylation and Postprenylation Processing in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Pathogenesis
title_short	Relative Contributions of Prenylation and Postprenylation Processing in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Pathogenesis
title_full	Relative Contributions of Prenylation and Postprenylation Processing in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Pathogenesis
title_fullStr	Relative Contributions of Prenylation and Postprenylation Processing in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Pathogenesis
title_full_unstemmed	Relative Contributions of Prenylation and Postprenylation Processing in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Pathogenesis
title_sort	relative contributions of prenylation and postprenylation processing in <named-content content-type="genus-species">cryptococcus neoformans</named-content> pathogenesis
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/f4899708ff68499aa223282fe1165f78
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Relative Contributions of Prenylation and Postprenylation Processing in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Pathogenesis

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