Autophagy, literally meaning “self-eating”, embraces three major intracellular pathways in eukaryotic cells, macroautophagy, microautophagy and chaperone-mediated autophagy (CMA), which share a common destiny of lysosomal degradation, but are mechanistically different from each other [1
]. During macroautophagy, intact organelles (such as mitochondria) and portions of the cytosol are sequestered into a double-membrane vesicle, termed an autophagosome. Subsequently, the completed autophagosome matures by fusing with an endosome and/or lysosome, thereby forming an autolysosome. This latter step exposes the cargo to lysosomal hydrolases to allow its breakdown, and the resulting macromolecules are transported back into the cytosol through membrane permeases for reuse (). By contrast, microautophagy involves the direct engulfment of cytoplasm at the lysosome surface, whereas CMA translocates unfolded, soluble proteins directly across the limiting membrane of the lysosome.
Schematic depiction of the autophagy pathway and its core molecular machinery in mammalian cells
In this review, we will focus on mammalian macroautophagy (hereafter referred to as autophagy), which plays important physiological roles in human health and disease. The basal, constitutive level of autophagy plays an important role in cellular homeostasis through the elimination of damaged/old organelles as well as the turnover of long-lived proteins and protein aggregates, and thus maintains quality control of essential cellular components. On the other hand, when cells encounter environmental stresses, such as nutrient starvation, hypoxia, oxidative stress, pathogen infection, radiation or anticancer drug treatment, the level of autophagy can be dramatically augmented as a cytoprotective response, resulting in adaptation and survival; however, dysregulated or excessive autophagy may lead to cell death. Thus, defective autophagy has been implicated in the pathogenesis of diverse diseases, such as certain types of neuronal degeneration and cancer, and also in aging [3
Although autophagy was first identified in mammalian cells approximately 50 years ago, our molecular understanding of it only started in the past decade, largely based on the discovery of autophagy-related (ATG
) genes initially in yeast followed by the identification of homologs in higher eukaryotes [4
]. Among these Atg proteins, one subset is essential for autophagosome formation, and is referred to as the “core” molecular machinery [5
]. These core Atg proteins are composed of four subgroups: (1) The Atg1/unc-51-like kinase (ULK) complex; (2) two ubiquitn-like protein (Atg12 and Atg8/LC3) conjugation systems; (3) the class III phosphatidylinositol 3-kinase (PtdIns3K)/Vps34 complex I; and (4) two transmembrane proteins, Atg9/mAtg9 (and associated proteins involved in its movement such as Atg18/WIPI-1) and VMP1. The proposed site for autophagosome formation, to which most of the core Atg proteins are recruited, is termed the phagophore assembly site (PAS).
In this review, we mainly highlight the recent advances in mammalian autophagy in terms of the molecular machinery involved in the formation and maturation of autophagosomes and the signaling cascades needed for the regulation of autophagy. The clarification of how autophagy is modulated in response to intracellular and extracellular stresses relies largely on the elucidation of the signaling network upstream of the Atg machinery.