Novel small molecule modulators of autophagy in yeast and mammalian systems

Abstract

"The term ‘Autophagy’ coined by Christian de Duve in 1963 derives its origin from the Greek words ‘auto’ and ‘phagy’ which literally translates to self-eating [1]. Macroautophagy (herein autophagy) is a cellular degradation pathway in which cytoplasmic components are captured in double membrane vesicles called ‘autophagosomes’ and delivered to lysosomes for degradation. The process of autophagy is evolutionarily conserved from yeast to mammals and has an indispensable role in maintaining cellular homeostasis. Around 38 autophagy related genes (ATGs) have been identified in Saccharomyces cerevisiae and Pichia pastoris and many of them are functionally conserved in higher eukaryotes [2]. Autophagy occurs at a basal rate in cells during normal growth conditions and is involved in degradation and removal of damaged or dead organelles and misfolded proteins [3]. The difference in levels of basal autophagy among different tissues was shown using transgenic mice expressing a fluorescent autophagosome marker. Basal autophagy levels were ranging from extremely low in brain, moderate in pancreatic acinar cells and relatively high in thymic epithelial cells [4]. Depending on how the cargo is sequestered, autophagy is of three types: Macroautophagy, microautophagy and chaperone mediated autophagy (CMA). Macroautophagy is the main autophagy pathway, in which cargo is sequestered in double membrane autophagosomes and taken to lysosomes. In microautophagy, the part of cytoplasm which needs to be degraded is directly engulfed in lysosome by invagination and folding of lysosomal membrane. In chaperone mediated autophagy (CMA), the protein cargo is recognised by the chaperone Hsc-70 which interacts with lysosomal membrane protein LAMP2A, unfolds the substrate protein, and transfers it across lysosomal membrane for degradation. Depending on the presence and absence of selectivity factors, autophagy is of two types: general and selective autophagy. Bulk degradation of long lived proteins and cytoplasmic components is called general autophagy. Selective autophagy involves specific recognition of cargo by autophagy receptors like p62, NBR1, Optineurin etc and their subsequent loading in autophagosomes [5]."