Autophagy, a process in which the lysosomes of cells capture, degrade and recycle cellular contents, such as cytosol and organelles, has been implicated in many diseases such as cancer, ageing, neurodegeneration, innate immunity and programmed cell death. It encompasses several autophagy- related pathways in which cargos are targeted for lysosomal turnover both selectively and non-selectively. The pathways in which cargos are degraded selectively include the cytosol to vacuole transport (Cvt) pathway and peroxisome turnover by micropexophagy and macropexophagy. Pexophagy contributes to virulence in fungal pathogens of plants and humans. Our long-term interest is to understand how the balance between organelle biogenesis and turnover contribute to organelle homeostasis, a phenomenon used by cells to respond to environmental cues. We have chosen to address this problem using peroxisomes and yeast as the model organism. Of the 33 autophagy-related proteins described to date, about half are involved in the core autophagic machinery involved in all autophagy-related pathways, while the others adapt this core machinery for the selective autophagy pathways. Our analysis of pexophagy- specific genes has revealed over half a dozen new proteins that are pexophagy-specific. We wish to elucidate mechanistically how these proteins adapt the autophagy machinery. In addition, we wish to understand the signaling pathways that trigger pexophagy, as well as the cross-talk between the peroxisome biogenesis and turnover machineries.
The Specific Aims of the proposal are to focus on the following topics: 1. Signaling events during pexophagy. 2. Nucleocytoplasmic shuttling of pexophagy-specific proteins and its physiological role. 3. Trafficking and role of Atg35 in pexophagy. 4. Ongoing functional analysis of pexophagy-specific proteins. 5. Inactivation and degradation of the docking complex of the peroxisome biogenesis machinery during pexophagy. 6. Connection between peroxisome inheritance and pexophagy.

Public Health Relevance

Our long-term interest is to understand how the balance between organelle synthesis and degradation contributes to the steady-state level of subcellular compartments, such as peroxisomes. This proposal seeks to understand the protein machinery involved in peroxisome degradation in response to environmental cues, focusing on the proteins and mechanisms involved, as well as the coordination between the peroxisome biogenesis and turnover machineries.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM069373-07
Application #
8310196
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Chin, Jean
Project Start
2006-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
7
Fiscal Year
2012
Total Cost
$306,900
Indirect Cost
$108,900
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
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
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
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
Till, Andreas; Lipinski, Simone; Ellinghaus, David et al. (2013) Autophagy receptor CALCOCO2/NDP52 takes center stage in Crohn disease. Autophagy 9:1256-7
Farre, 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
Subramani, Suresh; Malhotra, Vivek (2013) Non-autophagic roles of autophagy-related proteins. EMBO Rep 14:143-51
Till, Andreas; Lakhani, Ronak; Burnett, Sarah F et al. (2012) Pexophagy: the selective degradation of peroxisomes. Int J Cell Biol 2012:512721
Farre, Jean-Claude; Subramani, Suresh (2011) Rallying the exocyst as an autophagy scaffold. Cell 144:172-4
Manjithaya, Ravi; Subramani, Suresh (2011) Autophagy: a broad role in unconventional protein secretion? Trends Cell Biol 21:67-73
Nazarko, Volodymyr Y; Nazarko, Taras Y; Farre, Jean-Claude et al. (2011) Atg35, a micropexophagy-specific protein that regulates micropexophagic apparatus formation in Pichia pastoris. Autophagy 7:375-85

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