Relative contributions of prenylation and postprenylation processing in Cryptococcus neoformans pathogenesis

Shannon K. Esher, Kyla S. Ost, Lukasz Kozubowski, Dong Hoon Yang, Min Su Kim, Yong Sun Bahn, J. Andrew Alspaugh, Connie B. Nichols

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish
Article numbere00084-15
JournalmSphere
Volume1
Issue number2
DOIs
Publication statusPublished - 2016 Mar 1

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Molecular Biology

Fingerprint Dive into the research topics of 'Relative contributions of prenylation and postprenylation processing in Cryptococcus neoformans pathogenesis'. Together they form a unique fingerprint.

  • Cite this

    Esher, S. K., Ost, K. S., Kozubowski, L., Yang, D. H., Kim, M. S., Bahn, Y. S., Alspaugh, J. A., & Nichols, C. B. (2016). Relative contributions of prenylation and postprenylation processing in Cryptococcus neoformans pathogenesis. mSphere, 1(2), [e00084-15]. https://doi.org/10.1128/mSphere.00084-15