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Pathogenesis of thrombosis: cellular and pharmacogenetic contributions.

ABSTRACT: Our understanding of thrombosis formation has evolved significantly ever since physician Rudolf Virchow proposed his "triad" theory in 1856. Modern science has elucidated the mechanisms of stasis, hypercoagulability, and endothelial dysfunction. Today, we have a firm understanding of the key molecular factors involved in the coagulation cascade and fibrinolytic system, as well as the underlying genetic influences. This knowledge of cellular and genetic contributors has been translated into diverse pharmaceutical interventions. Here, we examine the molecular and cellular mechanisms of thrombosis and its associated pathologies. We also review the current state of pharmacologic interventions, including pro- and anti-thrombotics, direct oral anticoagulants, and anti-platelet therapies. The pharmacogenetic factors that guide clinical decision making and prognosis are described in detail. Finally, we explore new approaches to thrombosis drug discovery, repurposing, and diagnostics. We argue that network biology tools will enable a systems pharmacology revolution in the next generation of interventions, facilitating precision medicine applications and ultimately leading to improved patient outcomes.

SUBMITTER: Monie DD

PROVIDER: S-EPMC5778516 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Pathogenesis of thrombosis: cellular and pharmacogenetic contributions.

Monie Dileep D DD DeLoughery Emma P EP

Cardiovascular diagnosis and therapy 20171201 Suppl 3

Our understanding of thrombosis formation has evolved significantly ever since physician Rudolf Virchow proposed his "triad" theory in 1856. Modern science has elucidated the mechanisms of stasis, hypercoagulability, and endothelial dysfunction. Today, we have a firm understanding of the key molecular factors involved in the coagulation cascade and fibrinolytic system, as well as the underlying genetic influences. This knowledge of cellular and genetic contributors has been translated into diver ...[more]

PMID: 29399533

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Project description: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.

Dataset Information

Pathogenesis of thrombosis: cellular and pharmacogenetic contributions.

Publications

Pathogenesis of thrombosis: cellular and pharmacogenetic contributions.

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