Role of the mammalian ATG8/LC3 family in autophagy: differential and compensatory roles in the spatiotemporal regulation of autophagy

Abstract

Autophagy, an evolutionarily conserved cellular degradation pathway of the lysosome, is associated with many physiological and pathological processes. The hallmark of autophagy is the formation of the autophagosome that engulfs and degrades cytosolic components via its fusion with the lysosome, in either a selective or a non-selective manner. Autophagy is tightly regulated by proteins encoded by autophagy-related (atg) genes. Among these proteins, ATG8/ LC3 is essential for autophagosome biogenesis/maturation and it also functions as an adaptor protein for selective autophagy. In mammalian cells, several homologs of yeast Atg8 such as MAP1LC3, GABARAP, and GABARAPL 1/2 have been identified. However, the biological relevance of this gene diversity in higher eukaryotes, and their specific roles, are largely unknown. In this review, we describe the mammalian ATG8/LC3 family and discuss recent advancements in understanding their roles in the autophagic process. [BMB Reports 2016; 49(8): 424-430].

Fig. 1.. Domain structure of mammalian ATG8/LC3 family proteins. ATG8/LC3 family has an amino-terminal helix and a C-terminal ubiquitin core composed of β-strands with hydrophobic pockets. LC3/GABARAP(L)-I cleaved by ATG4 protease is conjugated to phosphatidylethanolamine (PE) to generate LC3II-PE. The arrow indicates the cleavage site of LC3/GABARAP(L) family proteins.

Fig. 2.. Differential/compensatory roles of the LC3 and GABARAP subfamilies during autophagy. (A) Autophagy can be induced in response to a variety of cellular stresses. Once autophagy is activated, it is executed in a multi-step processes including induction, formation/elongation/sealing of the isolation membrane, cargo selection/recruitment, transport/ fusion of the autophagosome, and cargo degradation in the autolysosome. (B) LC3, GABARAP, or GABARAPL, together with the autophagy core machinery proteins or specific proteins, regulate autophagosome biogenesis, cargo recognition/recruitment, transport, and fusion. Some functions, such as elongation of the membrane or cargo recruitment, are redundant between these proteins; however, other functions such as fusion or recruitment of specific cargo are differentially regulated by each ATG8/LC3 protein together with its interacting partners.