Autophagy fights disease through cellular self-digestion

Abstract

Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.

Figure 1. Different types of autophagy

Microautophagy refers to the sequestration of cytosolic components directly by lysosomes through invaginations in their limiting membrane. The function of this process in higher eukaryotes is not known, whereas microautophagy-like processes in fungi are involved in selective organelle degradation. In the case of macroautophagy, the cargoes are sequestered within a unique double-membrane cytosolic vesicle, an autophagosome. Sequestration can be either nonspecific, involving the engulfment of bulk cytoplasm, or selective, targeting specific cargoes such as organelles or invasive microbes. The autophagosome is formed by expansion of the phagophore, but the origin of the membrane is unknown. Fusion of the autophagosome with an endosome (not shown) or a lysosome provides hydrolases. Lysis of the autophagosome inner membrane and breakdown of the contents occurs in the autolysosome, and the resulting macromolecules are released back into the cytosol through membrane permeases. CMA involves direct translocation of unfolded substrate proteins across the lysosome membrane through the action of a cytosolic and lysosomal chaperone hsc70, and the integral membrane receptor LAMP-2A (lysosome-associated membrane protein type 2A).

Figure 2. A simplified model of autophagy regulation

Macroautophagy occurs at a basal level and can be induced in response to environmental signals including nutrients and hormones, and also microbial pathogens. The best-characterized regulatory pathway includes a class I PI3K and TOR, which act to inhibit autophagy, although the mechanism is not known. A class III PI3K is needed for activation of autophagy. TOR activity is probably regulated in part through feedback loops to prevent insufficient or excessive autophagy. For example, p70S6 kinase is a substrate of TOR that may act to limit TOR activity, ensuring basal levels of autophagy that are critical for homeostasis. Proteins in green and pink are stimulatory and inhibitory for autophagy, respectively. Dashed lines indicate possible regulatory effects.

Figure 3. The role of autophagy in human disease

Degradation, in particular through autophagy and the proteasome, is important in cellular physiology. Autophagy can act as a cytoprotective mechanism to prevent various diseases, and dysfunctional autophagy leads to pathology. In some cases, however, autophagy can be deleterious; for example, some microbes subvert autophagy for replication, and the cytoprotective action can allow cancer cells to resist anti-cancer treatments.

Figure 4. Autophagy and ageing

Defective lysosomal function has been reported in almost all tissues of ageing organisms, from nematode worms to mammals, and both macroautophagy and CMA activity decrease with age. Problems in the regulation and execution of macroautophagy contribute to its functional decline during ageing. Upregulation of macroautophagy by increased levels of glucagon in serum (that is, between meals) is lost in older organisms, possibly owing to persistently enhanced basal activity of the insulin receptor in response to the higher content of reactive oxygen species in ageing cells. Also, accumulation of undigested material (lipofuscin) inside secondary lysosomes (for example, autolysosomes) interferes with their ability to fuse with autophagosomes and to degrade their cargo. Changes with age in the lysosomal membrane make the CMA receptor unstable. The age-dependent decrease in the levels of this receptor is responsible for low CMA activity in older organisms. Some predicted consequences of the decline in autophagy with age are the inefficient clearance of damaged components, a poor response to stress, and a possible precipitating effect on disease.