The Elongator Complex Negatively Regulates Polarized Secretion

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Intracellular transport is fundamental for eukaryotic life and the function of regulators of transport is evolutionarily conserved. Rab proteins are a family of key regulators of vesicle and organelle transport, which aid in cell proliferation and cell survival. Functional conservation has allowed the simple single celled eukaryote, Saccharomyces cerevisiae to serve as a model system to study fundamental features of eukaryotes, including intracellular transport. An area of interest in the Collins laboratory is studying the signals that regulate membrane transport. The work presented in this thesis describes the negative regulation of exocytosis by the Elongator complex and the urmylation conjugation system. Deletion of the components of either system suppresses the temperature sensitivity of mutants defective in exocytosis. The Elongator complex has two proposed catalytic activities: acetyltransferase activity and SAM (S-adenosylmethionine) radical activity. We have found this complex is a cytoplasmic resident and therefore we propose that the relevant targets of these activities are in the cytoplasm or on cytoplasmic organelles that may influence membrane transport. Genetic analysis indicates that the profile of suppression of exocytic mutants caused by loss of Elongator complex function is similar to the suppression caused by overexpression of the exocytic Rab GTPase SEC4 and the t-SNARE SEC9. This suggests that the physiologic output of Elongator complex function may influence Sec4p function or SNARE function. These two functions are involved in the regulation of vesicle targeting and fusion, which may place Elongator function at this stage of the regulation of membrane transport. Other studies have reported that Elongator function also influences transcription and translation events. Our current model suggests that Elongator may serve as a signaling complex to regulate exocytosis in response to the translational capacity of the cell.

Intracellular transport is fundamental for eukaryotic life and the function of regulators of transport is evolutionarily conserved. Rab proteins are a family of key regulators of vesicle and organelle transport, which aid in cell proliferation and cell survival. Functional conservation has allowed the simple single celled eukaryote, Saccharomyces cerevisiae to serve as a model system to study fundamental features of eukaryotes, including intracellular transport. An area of interest in the Collins laboratory is studying the signals that regulate membrane transport. The work presented in this thesis describes the negative regulation of exocytosis by the Elongator complex and the urmylation conjugation system. Deletion of the components of either system suppresses the temperature sensitivity of mutants defective in exocytosis. The Elongator complex has two proposed catalytic activities: acetyltransferase activity and SAM (S-adenosylmethionine) radical activity. We have found this complex is a cytoplasmic resident and therefore we propose that the relevant targets of these activities are in the cytoplasm or on cytoplasmic organelles that may influence membrane transport. Genetic analysis indicates that the profile of suppression of exocytic mutants caused by loss of Elongator complex function is similar to the suppression caused by overexpression of the exocytic Rab GTPase SEC4 and the t-SNARE SEC9. This suggests that the physiologic output of Elongator complex function may influence Sec4p function or SNARE function. These two functions are involved in the regulation of vesicle targeting and fusion, which may place Elongator function at this stage of the regulation of membrane transport. Other studies have reported that Elongator function also influences transcription and translation events. Our current model suggests that Elongator may serve as a signaling complex to regulate exocytosis in response to the translational capacity of the cell.

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The American Heart Association Predoctoral Fellowship Program
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2007-11-06T16:39:59Z
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Exocytosis; Rab GTPase
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dissertation or thesis
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