Transporters, nutrient sensing and autophagy

点击翻译按钮获取中文摘要

ABSTRACT Autophagy is used by all cells to deliver cytoplasmic material to the lysosome for degradation. Significantly, autophagy has been implicated in several human diseases, including inflammatory disorders, cancer and neurodegeneration. Most of what we know about the regulation of autophagy is based on pioneering studies in yeast that defined the core autophagy machinery, but recent studies have revealed that autophagy has unique regulatory mechanisms in higher animals. Our hypothesis is that the regulation of autophagy in multicellular animals involves unknown mechanisms that integrate with known autophagy pathways. In support of our hypothesis, we recently identified previously uncharacterized genes encoding members of the solute transporter (SLC) family that are required for autophagy during salivary gland developmentally programmed cell death, including CG11665/hermes and CG5805. Significantly, hermes encodes a pyruvate transporter that is required for autophagy during salivary gland degradation. hermes mutant salivary glands have elevated mTOR signaling, and decreased mTOR function suppresses the hermes salivary gland phenotype. CG5805 encodes a putative mitochondrial amino acid transporter that is also required for autophagy in salivary glands. Our data suggests that the CG5805 and hermes salivary gland phenotypes are related, possibly through nutrient sensing mechanisms. In addition, hermes mutants have phenotypes suggesting the that these transporters may function in the regulation of autophagy in adult intestine stem cells. Our goal is to characterize the role of these SLCs in autophagy, cell health and death during development and adulthood. Here we propose to: (1) determine how Hermes regulates autophagy during development, (2) investigate CG5805 and its relationship to hermes and autophagy, and (3) characterize the role of transporters and autophagy in adult stem cell and intestine health. The association of autophagy with age-associated disorders illustrates the importance of investigating the relationship between autophagy, cell and animal health.