All subcellular organelles respond to intracellular or extracellular cues by modulation of their number, volume or enzymatic content. This ability to respond to their microenvironment allows cells to maintain organelle homeostasis, which is determined at steady-state by the balance between biogenesis and degradation. Peroxisome biogenesis, division and segregation require about 32 PEX genes, while peroxisome degradation by autophagic mechanisms (termed pexophagy) involves about 28 ATG, and about a dozen other, genes. Autophagy and pexophagy occur in many eukaryotes from yeast to mammals. Autophagy, as a field, has exploded in recent years with roles documented in cellular aging, cancer, cell development, neurodegenerative diseases, cell death, and in innate immunity against pathogens. After 15 years of work on the biogenesis of peroxisomes, we have embarked on parallel long- term studies of their turnover, to understand peroxisome homeostasis. The major questions addressed in this proposal are (1) How are peroxisomes targeted for micropexophagy and macropexophagy? (2) What protein-protein interactions and pathways target peroxisomes for degradation? (3) How is pexophagy controlled by production of PI-3-phosphate (PI-3P) by PI-3 kinase? (4) How does the production of PI-3P allow the recruitment and the downstream activation of other proteins involved in pexophagy? (5) How are the peroxisome biogenesis and turnover machineries coupled? This work not only addresses fundamental questions regarding how organelle homeostasis is maintained, but also deals with key proteins such as PI-3 Kinases and other autophagy-related proteins whose homologues are known to play important roles in development, cell death, aging and human diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM069373-01A2
Application #
7142097
Study Section
Special Emphasis Panel (ZRG1-CB-B (02))
Program Officer
Chin, Jean
Project Start
2006-08-01
Project End
2010-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
1
Fiscal Year
2006
Total Cost
$272,705
Indirect Cost
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Wang, W; Subramani, S (2017) Assays to Monitor Pexophagy in Yeast. Methods Enzymol 588:413-427
Burnett, Sarah F; Farré, Jean-Claude; Nazarko, Taras Y et al. (2015) Peroxisomal Pex3 activates selective autophagy of peroxisomes via interaction with the pexophagy receptor Atg30. J Biol Chem 290:8623-31
Till, Andreas; Saito, Rintaro; Merkurjev, Daria et al. (2015) Evolutionary trends and functional anatomy of the human expanded autophagy network. Autophagy 11:1652-67
Lakhani, Ronak; Vogel, Kara R; Till, Andreas et al. (2014) Defects in GABA metabolism affect selective autophagy pathways and are alleviated by mTOR inhibition. EMBO Mol Med 6:551-66
Nazarko, Taras Y; Ozeki, Katharine; Till, Andreas et al. (2014) Peroxisomal Atg37 binds Atg30 or palmitoyl-CoA to regulate phagophore formation during pexophagy. J Cell Biol 204:541-57
Cutting, Andrew S; Del Rosario, Yvette; Mu, Rong et al. (2014) The role of autophagy during group B Streptococcus infection of blood-brain barrier endothelium. J Biol Chem 289:35711-23
Ellinghaus, David; Zhang, Hu; Zeissig, Sebastian et al. (2013) Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies. Gastroenterology 145:339-47
Farré, Jean-Claude; Burkenroad, Aaron; Burnett, Sarah F et al. (2013) Phosphorylation of mitophagy and pexophagy receptors coordinates their interaction with Atg8 and Atg11. EMBO Rep 14:441-9
Till, Andreas; Lipinski, Simone; Ellinghaus, David et al. (2013) Autophagy receptor CALCOCO2/NDP52 takes center stage in Crohn disease. Autophagy 9:1256-7
Subramani, Suresh; Malhotra, Vivek (2013) Non-autophagic roles of autophagy-related proteins. EMBO Rep 14:143-51

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