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. ? ? ?
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