Each organelle of the cell has a unique lipid and protein composition that confers its specific functions. While much has been learned regarding the mechanisms that mediate sorting of proteins to different organelles, the mechanisms that govern the lipid content of organelles are largely unknown. New lipid synthesis occurs in the endoplasmic reticulum (ER), the Golgi apparatus, and the mitochondrion, and they are then distributed to other organelles. There are expansive gaps in knowledge regarding the mechanisms that coordinate the synthesis and distributions of lipids. The research proposed in this project focuses on sphingomyelin, a major structural component of the cellular membranes, and the Golgi apparatus, which functions as a ?lipid based sorting station? that disseminates lipids and proteins to nearly all organelles of the cell. Multiple types of cargo transport vesicles bud from the Golgi and it is widely thought that coalescence of lipids such as sphingolipids and cholesterol is a driving force for sorting of cargos into to transport pathways. Preliminary data document the engineering of a natural sphingomyelin-binding protein into a biosensor that enables analyses of sphingomyelin dynamics (synthesis, trafficking) in living cells. We will apply this new tool in fluorescence microscopy-based experiments to determine if sphingomyelin is enriched in distinct Golgi-to-plasma membrane transport carriers. Protein ?clients? of the sphingomyelin transport pathway will be identified using enzymatic proximity labeling and proteomic analyses, and sphingomyelin-dependent sorting mechanisms for these proteins will be elucidated. The research will provide new insights into the regulation and roles of sphingomyelin within the cell.

Public Health Relevance

The cell contains a set of internal compartments (called organelles) that exchange molecules. The proposed research addresses how protein and lipid molecules are trafficked between organelles. Defects in these pathways lead to cancer, Alzheimer?s and other neurological diseases, and cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM095766-08
Application #
10084172
Study Section
Membrane Biology and Protein Processing Study Section (MBPP)
Program Officer
Flicker, Paula F
Project Start
2011-09-30
Project End
2021-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
8
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Yale University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
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Ma, Mengxiao; Burd, Christopher G (2018) Lipids and proteins mix it up in Philly. Mol Biol Cell 29:694
Deng, Yongqiang; Rivera-Molina, Felix E; Toomre, Derek K et al. (2016) Sphingomyelin is sorted at the trans Golgi network into a distinct class of secretory vesicle. Proc Natl Acad Sci U S A 113:6677-82
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