Autophagy is a lysosome-mediated degradation process that involves the formation of an enclosed double-membrane autophagosome. Autophagy plays an important role in a wide variety of physiological processes in higher eukaryotes, including adaptation to various metabolic stress conditions, removal of aggregate-prone proteins and damaged organelles, and elimination of invading pathogens. Dysregulated autophagy activity has been linked to various pathologic conditions such as neurodegeneration, cardiomyopathy, and tumorigenesis.
Yeast genetic screens have laid the groundwork for a molecular understanding of autophagy. The autophagy process, however, exhibits fundamental differences between yeast and higher eukaryotes. We established C. elegans as a multicellular genetic model to delineate the autophagic machinery by demonstrating that a variety of protein aggregates are selectively removed by autophagy (a process termed aggrephagy) during embryogenesis. We carried out the first systematic genetic screens in multicellular organisms to identify essential autophagy genes. In addition to conserved and divergent homologs of yeast autophagy-related(Atg)genes, we isolated several autophagy genes conserved in higher eukaryotes but absent in yeast. The genetic hierarchy of autophagy genes in degradation of protein aggregates in C. elegans provides a framework for understanding the concerted action of autophagy genes in the aggrephagy pathway. We also investigated the physiological function of these metazoan-specific autophagy genes in mice.