Biological Functions of Autophagy Genes: A Disease Perspective

Abstract

The lysosomal degradation pathway of autophagy plays a fundamental role in cellular, tissue, and organismal homeostasis and is mediated by evolutionarily conserved autophagy-related (ATG) genes. Definitive etiological links exist between mutations in genes that control autophagy and human disease, especially neurodegenerative, inflammatory disorders and cancer. Autophagy selectively targets dysfunctional organelles, intracellular microbes, and pathogenic proteins, and deficiencies in these processes may lead to disease. Moreover, ATG genes have diverse physiologically important roles in other membrane-trafficking and signaling pathways. This Review discusses the biological functions of autophagy genes from the perspective of understanding-and potentially reversing-the pathophysiology of human disease and aging.

Figure 1.. Autophagy gene-dependent membrane trafficking pathways.

Shown are schematic illustrations of different membrane trafficking pathways that involve autophagy (ATG) proteins (green ovals). See text for explanations of each pathway and a discussion of their physiological functions. See Table 1 for examples of genetic mutations that impair autophagy-related pathways which are associated with human disease. The major type of autophagy, macroautophagy, is labeled as “classical degradative autophagy” to distinguish it from other trafficking pathways that utilize overlapping ATG proteins. Due to space limitations, not all ATG proteins, proteins involved in vesicle fusion, or secretary cargo are depicted. PM, plasma membrane. LC3-II (green circle) is the phosphatidyl-ethanolamine-conjugated form of the autophagy protein, LC3.

Figure 2.. Conceptual overview of selective autophagy.

Shown are the diverse cargoes that are degraded by autophagy and the major known mechanisms by which cargo are attached to LC3 or GABARAP family members on the phagophore membrane. Also listed are currently known organelle-specific LC3/GABARAP-binding proteins, tags that label cargo destined for selective autophagic degradation, LC3/GABRAP-binding adaptor proteins, and factors that regulate the recognition of cargo by adaptors or LC3/GABARAP. Organelle-specific LC3/GABARAP-binding proteins and LC3/GABARAP-binding adaptor proteins interact with LC3/GABARAP via conserved W/F/YxxL/I/V motifs. See Table 2 for information about different types of selective autophagy and their possible roles in physiology and disease.

Figure 3.. Diverse biological functions of autophagy genes contribute to their roles in the regulation of mammalian disease.

Shown are the major known biological functions of ATG genes and the broad categories of diseases that they regulate as predicted based on mouse experimental data and human genetic associations. Below major disease categories, some representative specific diseases are noted. Many other examples exist but are not shown due to space limitations.