The objective of the proposed research is to undertake a detailed analysis of an under investigated class of proteins: the phosphatidylinositol (PtdIns/ phosphatidylcholine (PtdCho) transfer proteins (PITPs). To this end, we will primarily employ the prototypical member of the Sec14-superfamily as experimental model. Our data indicate that the yeast PITP (Sec14) is an essential factor that operates at the interface of phospholipid metabolism and Golgi/endosomal membrane trafficking functions. The proposed studies will test specific hypotheses that relate to: (i) how the Sec14-like 'nanoreactor'proteins bind and exchange their lipid ligands, (ii) the mechanisms by which two non-canonical Sec14-like proteins regulate specific steps of lipid metabolism in yeast, and (iii) how the oxysterol binding protein (OSBP)-related Kes1 antagonizes Sec14-dependent PtdIns-4-phosphate signaling in Golgi/endosomal membranes and how this lipid binding protein antagonism is played out in the dual lipid binding properties of these proteins. These studies will clarify key unanswered questions regarding the mechanism of function of the Sec14 itself, the mechanisms by which Sec14-like proteins couple lipid metabolism to PtdIns kinase signaling, and more global ramifications of PITP functional interactions with the oxysterol binding protein family members (ORPs). The available evidence suggests that PITPs and ORPs play central, and previously unrecognized, roles in lipid-mediated signal transduction processes that interface with such diverse cellular processes as protein secretion, photo-transduction, receptor-mediated signaling, cell-cycle control, and basic lipid metabolism. A growing number of inherited neurodegenerative diseases, and diseases of proliferative disorders (e.g. cancer), are attributed to insufficiencies in PITPs and other Sec14-like proteins. Thus, the proposed studies will provide new and fundamental information that bears directly on molecular mechanisms by which PITPs, and Kes1-like OSBPs, regulate signal transduction in eukaryotes and protect mammals from diseases of deranged cell proliferation and neurodegeneration.

Public Health Relevance

Neurodegenerative disorders and cancer are two examples of pathological states where deficiencies in cellular signaling processes result in human disease. The former are a result of premature cell death, while the latter results from inappropriate cell growth. The proposed studies will help define the mechanisms by which lipid signaling pathways are regulated by a novel class of proteins - the Sec14- like PITPs. Since the pathways to be studied are of direct relevance to neurodegenerative diseases and cancer, it is hoped the new and fundamental information that will derive from these studies will instruct development of new therapies for these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM044530-22
Application #
8605191
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Chin, Jean
Project Start
1991-07-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
22
Fiscal Year
2014
Total Cost
$290,809
Indirect Cost
$90,247
Name
Texas A&M University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
Huang, Jin; Ghosh, Ratna; Tripathi, Ashutosh et al. (2016) Two-ligand priming mechanism for potentiated phosphoinositide synthesis is an evolutionarily conserved feature of Sec14-like phosphatidylinositol and phosphatidylcholine exchange proteins. Mol Biol Cell 27:2317-30
Khan, Danish; McGrath, Kaitlyn R; Dorosheva, Oleksandra et al. (2016) Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors. J Lipid Res 57:650-62
Ghosh, Ratna; de Campos, Marília K F; Huang, Jin et al. (2015) Sec14-nodulin proteins and the patterning of phosphoinositide landmarks for developmental control of membrane morphogenesis. Mol Biol Cell 26:1764-81
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Nile, Aaron H; Tripathi, Ashutosh; Yuan, Peihua et al. (2014) PITPs as targets for selectively interfering with phosphoinositide signaling in cells. Nat Chem Biol 10:76-84
Ren, Jihui; Pei-Chen Lin, Coney; Pathak, Manish C et al. (2014) A phosphatidylinositol transfer protein integrates phosphoinositide signaling with lipid droplet metabolism to regulate a developmental program of nutrient stress-induced membrane biogenesis. Mol Biol Cell 25:712-27
Tripathi, Ashutosh; Nile, Aaron H; Bankaitis, Vytas A (2014) Sec14-like phosphatidylinositol-transfer proteins and diversification of phosphoinositide signalling outcomes. Biochem Soc Trans 42:1383-8
Lee, Anna Y; St Onge, Robert P; Proctor, Michael J et al. (2014) Mapping the cellular response to small molecules using chemogenomic fitness signatures. Science 344:208-11
Bankaitis, Vytas A; Garcia-Mata, Rafael; Mousley, Carl J (2012) Golgi membrane dynamics and lipid metabolism. Curr Biol 22:R414-24
Bankaitis, Vytas A; Ile, Kristina E; Nile, Aaron H et al. (2012) Thoughts on Sec14-like nanoreactors and phosphoinositide signaling. Adv Biol Regul 52:115-21

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