Eaten alive: novel insights into autophagy from multicellular model systems

Abstract

Autophagy delivers cytoplasmic material to lysosomes for degradation. First identified in yeast, the core genes that control this process are conserved in higher organisms. Studies of mammalian cell cultures have expanded our understanding of the core autophagy pathway, but cannot reveal the unique animal-specific mechanisms for the regulation and function of autophagy. Multicellular organisms have different types of cells that possess distinct composition, morphology, and organization of intracellular organelles. In addition, the autophagic machinery integrates signals from other cells and environmental conditions to maintain cell, tissue and organism homeostasis. Here, we highlight how studies of autophagy in flies and worms have identified novel core autophagy genes and mechanisms, and provided insight into the context-specific regulation and function of autophagy.

Keywords: Caenorhabditis elegans; Drosophila melanogaster; aggrephagy; autophagy.

Figure 1

Aggrephagy pathway in C. elegans. Selective removal of protein aggregates requires the hierarchical recruitment of receptor and scaffold proteins. Different scaffold proteins mediate the degradation of different cargo/receptor complexes. In degradation of PGL granules, arginine methylated PGL-1 and PGL-3, a process mediated by the C. elegans arginine methyltransferase PRMT1 homolog EPG-11, are recruited into SEPA-1 aggregates, which further associate with the scaffold protein EPG-2. The scaffold protein EPG-7 mediates the degradation of SQST-1. The cargo/receptor/scaffold complex recruits ATG proteins to trigger the formation of surrounding autophagosomal membranes. Genetic screens also identified several metazoan specific autophagy genes that are essential for degradation of both PGL granules and SQST-1 aggregates. The mammalian homologs of these genes are also required for the basal level of autophagy. EPG-3, -4, and -6 are involved in progression of omegasomes to isolation membranes/autophagosomes. EPG-5 is required for the formation of degradative autolysosomes. CUP-5 is essential for lysosomal function. ATG,; EPG,; PGL,; PRMT,; SEPA,; SQST,.

Figure 2

Regulation of autophagy activity. The mTORC1 and the VPS34/PI(3)P regulatory complexes have been shown to be the two most extensively studied nodes for integrating the status of nutrients, cellular energy, and growth factors with the autophagosome initiation. Nutrient status also regulates autophagosome maturation by regulating O-GlcNAylation of SNAP-29. Under starvation conditions, levels of UDP-GlcNAc are decreased, resulting in reduction of O-GlcNAc-modified SNAP-29 levels. Unmodified SNAP-29 forms a more stable SNARE complex with autophagosome-localized Stx17 and lysosomal VAMP8 to mediate the fusion of autophagosomes with endosomes/lysosomes. Starvation and other autophagy stimuli may also directly regulate OGT activity. Autophagy activity is also regulated by calcium signaling. In flies, the miRNA miR14 regulates translation of ip3k2 and IP3 levels in cells to control calcium levels and autophagy. IP3, inositol-1,4,5 trisphosphate; mTORC1, mammalian target of rapamycin serine/threonine kinase complex 1; OGT,; PI(3)P,; SNAP,; SNARE,; Stx,; VAMP,; VPS,.