Understanding and Exploiting Protein Prenyltransferases

Nguyen, Uyen; Goody, Roger S.; Alexandrov, Kirill

doi:10.1002/cbic.200900727

Cited by 48 publications

(40 citation statements)

References 106 publications

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“…We hypothesized that the cdc43⌬ mutant phenotypes were due to mislocalization of one or more Ggtase-I substrates. Small GTPases constitute an important group of prenylated proteins that require membrane localization to be fully functional (1,44). In C. neoformans, growth and morphology are maintained at elevated temperatures by the coordinated action of several GTPases.…”

Section: Resultsmentioning

confidence: 99%

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Restricted Substrate Specificity for the Geranylgeranyltransferase-I Enzyme in Cryptococcus neoformans: Implications for Virulence

et al. 2013

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Proper cellular localization is required for the function of many proteins. The CaaX prenyltransferases (where CaaX indicates a cysteine followed by two aliphatic amino acids and a variable amino acid) direct the subcellular localization of a large group of proteins by catalyzing the attachment of hydrophobic isoprenoid moieties onto C-terminal CaaX motifs, thus facilitating membrane association. This group of enzymes includes farnesyltransferase (Ftase) and geranylgeranyltransferase-I (Ggtase-1). Classically, the variable (X) amino acid determines whether a protein will be an Ftase or Ggtase-I substrate, with Ggtase-I substrates often containing CaaL motifs. In this study, we identify the gene encoding the ␤ subunit of Ggtase-I (CDC43) and demonstrate that Ggtase-mediated activity is not essential. However, Cryptococcus neoformans CDC43 is important for thermotolerance, morphogenesis, and virulence. We find that Ggtase-I function is required for full membrane localization of Rho10 and the two Cdc42 paralogs (Cdc42 and Cdc420). Interestingly, the related Rac and Ras proteins are not mislocalized in the cdc43⌬ mutant even though they contain similar CaaL motifs. Additionally, the membrane localization of each of these GTPases is dependent on the prenylation of the CaaX cysteine. These results indicate that C. neoformans CaaX prenyltransferases may recognize their substrates in a unique manner from existing models of prenyltransferase specificity. It also suggests that the C. neoformans Ftase, which has been shown to be more important for C. neoformans proliferation and viability, may be the primary prenyltransferase for proteins that are typically geranylgeranylated in other species.

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Section: Resultsmentioning

confidence: 99%

“…A prenyltransferase can bind to this motif and covalently attach an isoprenoid group onto the CaaX-box cysteine. This modification is irreversible and is often essential for stable membrane localization (1)(2)(3).…”

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confidence: 99%

Restricted Substrate Specificity for the Geranylgeranyltransferase-I Enzyme in Cryptococcus neoformans: Implications for Virulence

et al. 2013

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“…8). Protein prenyltransferases occur as heterodimers with a common a-subunit and b-subunits specific for each enzyme (Nguyen et al, 2010). The expression of the three genes encoding three subunits was evaluated by quantitative real-time PCR: a (Nt-a), b-farnesyl (Nt-bF), and b-geranylgeranyl (Nt-bGG).…”

Section: Activities Of N Tabacum Protein Prenyltransferases Are Inhimentioning

confidence: 99%

S-Carvone Suppresses Cellulase-Induced Capsidiol Production in Nicotiana tabacum by Interfering with Protein Isoprenylation

et al. 2013

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(C.G., D.T., M.R.)S-Carvone has been described as a negative regulator of mevalonic acid (MVA) production by interfering with 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) activity, a key player in isoprenoid biosynthesis. The impact of this monoterpene on the production of capsidiol in Nicotiana tabacum, an assumed MVA-derived sesquiterpenoid phytoalexin produced in response to elicitation by cellulase, was investigated. As expected, capsidiol production, as well as early stages of elicitation such as hydrogen peroxide production or stimulation of 5-epi-aristolochene synthase activity, were repressed. Despite the lack of capsidiol synthesis, apparent HMGR activity was boosted. Feeding experiments using (1-13 C)Glc followed by analysis of labeling patterns by 13 C-NMR, confirmed an MVA-dependent biosynthesis; however, treatments with fosmidomycin, an inhibitor of the MVA-independent 2-Cmethyl-D-erythritol 4-phosphate (MEP) isoprenoid pathway, unexpectedly down-regulated the biosynthesis of this sesquiterpene as well. We postulated that S-carvone does not directly inhibit the production of MVA by inactivating HMGR, but possibly targets an MEP-derived isoprenoid involved in the early steps of the elicitation process. A new model is proposed in which the monoterpene blocks an MEP pathway-dependent protein geranylgeranylation necessary for the signaling cascade. The production of capsidiol was inhibited when plants were treated with some inhibitors of protein prenylation or by further monoterpenes. Moreover, S-carvone hindered isoprenylation of a prenylable GFP indicator protein expressed in N. tabacum cell lines, which can be chemically complemented with geranylgeraniol. The model was further validated using N. tabacum cell extracts or recombinant N. tabacum protein prenyltransferases expressed in Escherichia coli. Our study endorsed a reevaluation of the effect of S-carvone on plant isoprenoid metabolism.

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“…Sterol metabolites form a crucial component of cellular membranes and lipid droplets. In addition, farnesylpyrophosphate and geranylpyrophosphate, intermediates from the mevalonate pathway, act as substrates for protein prenylation, an important post-translational modification (Nguyen et al 2010). Therefore, maintenance of sterol homeostasis represents a critical cellular process.…”

Section: Hc: Oxysterol Regulator Of Sterol Homeostasismentioning

confidence: 99%

Armand-Frappier Outstanding Student Award — The emerging role of 25-hydroxycholesterol in innate immunity

2015

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Abstract:The metabolic interplay between hosts and viruses plays a crucial role in determining the outcome of viral infection. Viruses reorchestrate the host's primary metabolic gene networks, including genes associated with mevalonate and isoprenoid synthesis, to acquire the necessary energy and structural components for their viral life cycles. Recent work has demonstrated that the interferon-mediated antiviral response suppresses the sterol pathway through production of a signalling molecule, 25-hydroxycholesterol (25HC). This oxysterol has been shown to exert multiple effects, both through incorporation into host cellular membranes as well as through transcriptional control. Herein, we summarize our current understanding of the multifunctional roles of 25HC in the mammalian innate antiviral response.Key words: 25-hydroxycholesterol, cholesterol-25-hydroxylase, metabolism, virus, immunity.Résumé : Les interactions métaboliques entre les hôtes et les virus jouent un rôle crucial qui déterminera l'issue de l'infection virale. Les virus réorganisent les réseaux de gènes métaboliques primaires de l'hôte, dont les gènes liés à la synthèse du mévalonate et des isoprénoïdes, afin d'acquérir l'énergie et les éléments structuraux néces-saires à leur cycle de vie. Des travaux récents ont démontré que la réponse antivirale activée par les interférons supprime la voie des stérols par la production d'une molécule de signalisation, le 25-hydroxycholestérol (25HC). On a révélé que cet oxystérol avait plus d'un effet, tant par son intégration dans les membranes de la cellule-hôte que par le contrôle de la transcription. Nous résumons ici notre conception actuelle des rôles multifonctionnels du 25HC dans la réponse antivirale innée chez les mammifères. [Traduit par la Rédaction] -clés : 25-hydroxycholestérol, cholestérol-25-hydroxylase, métabolisme, virus, immunité. Mots

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Understanding and Exploiting Protein Prenyltransferases

Cited by 48 publications

References 106 publications

Restricted Substrate Specificity for the Geranylgeranyltransferase-I Enzyme in Cryptococcus neoformans: Implications for Virulence

Restricted Substrate Specificity for the Geranylgeranyltransferase-I Enzyme in Cryptococcus neoformans: Implications for Virulence

S-Carvone Suppresses Cellulase-Induced Capsidiol Production in Nicotiana tabacum by Interfering with Protein Isoprenylation

Armand-Frappier Outstanding Student Award — The emerging role of 25-hydroxycholesterol in innate immunity

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