Autophagy: cellular and molecular mechanisms

Abstract

Autophagy is a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is generally thought of as a survival mechanism, although its deregulation has been linked to non-apoptotic cell death. Autophagy can be either non-selective or selective in the removal of specific organelles, ribosomes and protein aggregates, although the mechanisms regulating aspects of selective autophagy are not fully worked out. In addition to elimination of intracellular aggregates and damaged organelles, autophagy promotes cellular senescence and cell surface antigen presentation, protects against genome instability and prevents necrosis, giving it a key role in preventing diseases such as cancer, neurodegeneration, cardiomyopathy, diabetes, liver disease, autoimmune diseases and infections. This review summarizes the most up-to-date findings on how autophagy is executed and regulated at the molecular level and how its disruption can lead to disease.

Figure 1

Molecular circuitry and signalling pathways regulating autophagy. Autophagy is a complex self-degradative process that involves the following key steps: (a) control of phagophore formation by Beclin-1/VPS34 at the ER and other membranes in response to stress signalling pathways; (b) Atg5–Atg12 conjugation, interaction with Atg16L and multimerization at the phagophore; (c) LC3 processing and insertion into the extending phagophore membrane; (d) capture of random or selective targets for degradation, completion of the autophagosome accompanied by recycling of some LC3-II/ATG8 by ATG4, followed by; (e) fusion of the autophagosome with the lysosome and proteolytic degradation by lysosomal proteases of engulfed molecules. Autophagy is regulated by important signalling pathways in the cell, including stress-signalling kinases such as JNK-1, which promotes autophagy by phosphorylating Bcl-2, thereby promoting the interaction of Beclin-1 with VPS34 [31]. Perhaps the central signalling molecule in determining the levels of autophagy in cells is the mTOR kinase that likely mediates its effects on autophagy through inhibition of ATG1/Ulk-1/-2 complexes at the earliest stages in phagophore formation from lipid bilayers [6]. mTOR is key to integrating metabolic, growth factor and energy signalling into levels of both autophagy, on the one hand, which is inhibited by mTOR when nutrients are plentiful and, on the other hand, to growth-promoting activities, including protein translation, that are stimulated by mTOR signalling [16]. Autophagy is induced by hypoxia and low cytosolic ATP levels that feed through REDD1 and AMP-kinase to inhibit mTOR activity through reduced Rheb GTPase activity. Conversely, autophagy is inhibited by increased growth factor signalling through the insulin receptor and its adaptor, IRS1, as well as other growth factor receptors that activate the Class I group of PI3-kinases and Akt, to promote mTOR activity through inhibition of TSC1/TSC2 and increased Rheb GTPase activity [16,73].