The Arf family of regulatory GTPases, within the Ras superfamily, emerged in prokaryotes and members of the Arf family, Arfs and Arl2, have been implicated as critical components in the endosymbiotic origins of eukaryotes. As such they are predicted to have essential roles in the regulation of cell biology in all eukaryotes. We and others have previously provided evidence for a role for Arl2 in microtubule growth in cells but more recently we have discovered an obligate role for Arl2 in maintenance of energy (ATP) levels that is predicted to be its fundamental role in eukaryotes. In this application I propose to develop molecular models of Arl2 regulation of ATP levels, as well as for the newly identified Arl2 GAPs/effectors in the ELMO (Engulfment and cell motility) family, that regulate mitochondria and Golgi morphology. This application has three specific aims. (1) Determine the role of Arl2 in maintenance of ATP levels. (2) Characterize the GAP domain of ELMOD2 and its actions in mitochondria including specifically its role in mitochondrial morphology. (3) Determine the specificity and functions of ELMOD1. I hypothesize that ELMOD1 acts in cells as an ArfGAP that can attenuate Arf signaling at the Golgi and impact membrane traffic also at the TGN, where it has effector properties. Together these aims will provide detailed molecular models of an ancient means of regulating energy metabolism in perhaps all eukaryotic cells, with ties to cell division, the cytoskeleton, and the regulation of gene transcription in the nucleus. These studies have the potential to fundamentally alter our understanding of essential cellular processes with ties to energy metabolism, cancer, sensitivity to cancer chemotherapeutics, and gene transcription.

Public Health Relevance

Maintenance of proper energy balance is essential to the health and function of all cells and is the primary responsibility of mitochondria, the site of chemical energy (ATP) generation and oxygen consumption. Dramatic changes in energy utilization are known to accompany chronic diseases including cancer, neurodegenerative diseases, and diabetes. We have discovered novel signaling pathways that are involved in regulating cellular ATP levels and the morphology of the mitochondria and Golgi compartments that are tied to the ancient and highly conserved regulatory GTPase Arl2. In this application I propose three specific aims that will elucidate molecular mechanisms of Arl2 and Arl2 GTPase activating protein actions as regulators of ATP production, mitochondria morphology, and Golgi integrity with predicted links to cell division and the cell cytoskeleton.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular and Integrative Signal Transduction Study Section (MIST)
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Gerratana, Barbara
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Emory University
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Newman, Laura E; Schiavon, Cara R; Turn, Rachel E et al. (2017) The ARL2 GTPase regulates mitochondrial fusion from the intermembrane space. Cell Logist 7:e1340104
Francis, Joshua W; Newman, Laura E; Cunningham, Leslie A et al. (2017) A Trimer Consisting of the Tubulin-specific Chaperone D (TBCD), Regulatory GTPase ARL2, and ?-Tubulin Is Required for Maintaining the Microtubule Network. J Biol Chem 292:4336-4349
Francis, Joshua W; Goswami, Devrishi; Novick, Scott J et al. (2017) Nucleotide Binding to ARL2 in the TBCD?ARL2??-Tubulin Complex Drives Conformational Changes in ?-Tubulin. J Mol Biol 429:3696-3716
Bhatt, Jay M; Viktorova, Ekaterina G; Busby, Theodore et al. (2016) Oligomerization of the Sec7 domain Arf guanine nucleotide exchange factor GBF1 is dispensable for Golgi localization and function but regulates degradation. Am J Physiol Cell Physiol 310:C456-69
Wigington, Callie P; Morris, Kevin J; Newman, Laura E et al. (2016) The Polyadenosine RNA-binding Protein, Zinc Finger Cys3His Protein 14 (ZC3H14), Regulates the Pre-mRNA Processing of a Key ATP Synthase Subunit mRNA. J Biol Chem 291:22442-22459
Francis, Joshua W; Turn, Rachel E; Newman, Laura E et al. (2016) Higher order signaling: ARL2 as regulator of both mitochondrial fusion and microtubule dynamics allows integration of 2 essential cell functions. Small GTPases 7:188-196
Seixas, CecĂ­lia; Choi, Soo Young; Polgar, Noemi et al. (2016) Arl13b and the exocyst interact synergistically in ciliogenesis. Mol Biol Cell 27:308-20
Flex, Elisabetta; Niceta, Marcello; Cecchetti, Serena et al. (2016) Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy. Am J Hum Genet 99:962-973
Newman, Laura E; Schiavon, Cara; Kahn, Richard A (2016) Plasmids for variable expression of proteins targeted to the mitochondrial matrix or intermembrane space. Cell Logist 6:e1247939
Kahn, Richard A; Lambright, David G (2015) A PH Domain with Dual Phospholipid Binding Sites Regulates the ARF GAP, ASAP1. Structure 23:1971-3

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