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)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM061221-15S1
Application #
8898308
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Ainsztein, Alexandra M
Project Start
2000-09-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
15
Fiscal Year
2014
Total Cost
$26,288
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
06520
Zhang, Pengwei; Monteiro da Silva, Gabriel; Deatherage, Catherine et al. (2018) Cell-Penetrating Peptide Mediates Intracellular Membrane Passage of Human Papillomavirus L2 Protein to Trigger Retrograde Trafficking. Cell 174:1465-1476.e13
Deng, Yongqiang; Pakdel, Mehrshad; Blank, Birgit et al. (2018) Activity of the SPCA1 Calcium Pump Couples Sphingomyelin Synthesis to Sorting of Secretory Proteins in the Trans-Golgi Network. Dev Cell 47:464-478.e8
Ma, Mengxiao; Kumar, Santosh; Purushothaman, Latha et al. (2018) Lipid trafficking by yeast Snx4 family SNX-BAR proteins promotes autophagy and vacuole membrane fusion. Mol Biol Cell 29:2190-2200
Cui, Tie-Zhong; Peterson, Tabitha A; Burd, Christopher G (2017) A CDC25 family protein phosphatase gates cargo recognition by the Vps26 retromer subunit. Elife 6:
Ma, Mengxiao; Burd, Christopher G; Chi, Richard J (2017) Distinct complexes of yeast Snx4 family SNX-BARs mediate retrograde trafficking of Snc1 and Atg27. Traffic 18:134-144
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
Popa, Andreea; Zhang, Wei; Harrison, Megan S et al. (2015) Direct binding of retromer to human papillomavirus type 16 minor capsid protein L2 mediates endosome exit during viral infection. PLoS Pathog 11:e1004699
DiMaio, Daniel; Burd, Christopher G; Goodner, Kylia (2015) Riding the R Train into the Cell. PLoS Pathog 11:e1005036
Chi, Richard J; Harrison, Megan S; Burd, Christopher G (2015) Biogenesis of endosome-derived transport carriers. Cell Mol Life Sci 72:3441-3455
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

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