| Title: | Relative Contributions of Prenylation and Postprenylation Processing in Cryptococcus neoformans Pathogenesis |
| Author(s): | Esher SK; Ost KS; Kozubowski L; Yang DH; Kim MS; Bahn YS; Alspaugh JA; Nichols CB; |
| Address: | "Departments of Molecular Genetics and Microbiology/Medicine, Duke University School of Medicine, Durham, North Carolina, USA. Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, USA. Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea" |
| ISSN/ISBN: | 2379-5042 (Print) 2379-5042 (Electronic) 2379-5042 (Linking) |
| 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 beta-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" |
| Keywords: | Cryptococcus neoformans Ras-like GTPases farnesyltransferase fungal pathogen protein prenylation; |
| Notes: | "PubMed-not-MEDLINEEsher, Shannon K Ost, Kyla S Kozubowski, Lukasz Yang, Dong-Hoon Kim, Min Su Bahn, Yong-Sun Alspaugh, J Andrew Nichols, Connie B eng P01 AI104533/AI/NIAID NIH HHS/ R01 AI050128/AI/NIAID NIH HHS/ S10 RR027528/RR/NCRR NIH HHS/ T32 GM007184/GM/NIGMS NIH HHS/ 2016/06/16 mSphere. 2016 Mar 30; 1(2):e00084-15. doi: 10.1128/mSphere.00084-15. eCollection 2016 Mar-Apr" |
