The broad goal of this research project is to elucidate the mechanisms by which proteins and lipids in the endosome are packaged into transport carriers that bud from the endosome and ferry cargo to the Golgi apparatus and other organelles. These trafficking pathways, collectively termed 'endosomal retrograde transport,'are vital for cell physiology and homeostasis, metazoan development and they counter poorly understood processes that contribute to lysosomal storage diseases, cancer, Alzheimer's disease, and other diseases. In previous funding cycles we discovered that retrograde pathways are used to modulate the composition of the plasma membrane in response to environmental and nutritional cues, and we established roles for a soluble protein sorting complex called 'retromer'and three effectors of Phosphatidylinositol 3-kinase (PI3K) called sorting nexin (SNX) proteins. These components assemble on the endosome membrane where they capture and package cargo into budding transport carriers but the underlying mechanisms are unknown. With the principle cellular function of retromer now well established, the major challenge for the field is to elucidate the mechanisms by which it functions. Biochemical approaches will be used to dissect the mechanism of retromer assembly with cargo on the endosome membrane. These experiments will complemented with live cell imaging of retrograde transport that will place the assembly reactions in a physiological context. In recognition that the retromer sorting nexins are members of a much larger SNX protein family for which the functions of all but a few have been described, unbiased, proteome scale experiments will be used to elucidate the functions of each sorting nexin and to assess their specific contributions to cell physiology.

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)
Type
Research Project (R01)
Project #
5R01GM061221-15
Application #
8725672
Study Section
Membrane Biology and Protein Processing Study Section (MBPP)
Program Officer
Ainsztein, Alexandra M
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Harrison, Megan S; Hung, Chia-Sui; Liu, Ting-ting et al. (2014) A mechanism for retromer endosomal coat complex assembly with cargo. Proc Natl Acad Sci U S A 111:267-72
Burd, Christopher; Cullen, Peter J (2014) Retromer: a master conductor of endosome sorting. Cold Spring Harb Perspect Biol 6:
Chi, Richard J; Liu, Jingxuan; West, Matthew et al. (2014) Fission of SNX-BAR-coated endosomal retrograde transport carriers is promoted by the dynamin-related protein Vps1. J Cell Biol 204:793-806
Graham, Todd R; Burd, Christopher G (2011) Coordination of Golgi functions by phosphatidylinositol 4-kinases. Trends Cell Biol 21:113-21
Burd, Christopher G (2011) Physiology and pathology of endosome-to-Golgi retrograde sorting. Traffic 12:948-55
Wood, Christopher S; Schmitz, Karl R; Bessman, Nicholas J et al. (2009) PtdIns4P recognition by Vps74/GOLPH3 links PtdIns 4-kinase signaling to retrograde Golgi trafficking. J Cell Biol 187:967-75
Strochlic, Todd I; Schmiedekamp, Briana C; Lee, Jacqueline et al. (2008) Opposing activities of the Snx3-retromer complex and ESCRT proteins mediate regulated cargo sorting at a common endosome. Mol Biol Cell 19:4694-706
Schmitz, Karl R; Liu, Jingxuan; Li, Shiqing et al. (2008) Golgi localization of glycosyltransferases requires a Vps74p oligomer. Dev Cell 14:523-34
Liu, Jingxuan; Sitaram, Anand; Burd, Christopher G (2007) Regulation of copper-dependent endocytosis and vacuolar degradation of the yeast copper transporter, Ctr1p, by the Rsp5 ubiquitin ligase. Traffic 8:1375-84
Strochlic, Todd I; Setty, Thanuja Gangi; Sitaram, Anand et al. (2007) Grd19/Snx3p functions as a cargo-specific adapter for retromer-dependent endocytic recycling. J Cell Biol 177:115-25

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