Cell homeostasis is achieved by balancing biosynthesis and turnover. In eukaryotic cells, the lysosome (or the analogous yeast and plant vacuole) is the primary organelle for degradation through its wide array of resident acid hydrolases. As an adaptive response in unfavorable conditions such as nutrient deprivation, autophagy mediates a highly regulated self-eating process via lysosomes. Double-membrane vesicles, termed autophagosomes, engulf long-lived proteins, damaged organelles, and even invasive pathogens, and transport these cargos to the lysosomes. There, the outer-membrane of the autophagosome fuses with the lysosomal membrane, and the inner vesicle, together with its cargo, is degraded (). The resulting macromolecules can be recycled back to the cytosol for reuse during starvation (165
). Malfunction of autophagy contributes to a variety of diseases, including cancer, neurodegeneration, cardiovascular disorders, and microbe infection, because efficient sequestration and clearance of unneeded or damaged cellular or nonself components is crucial for cell survival and function.
Figure 1 Schematic model of autophagy. The class III PtdIns3K complex mediates nucleation of the phagophore membrane, enwrapping cytosolic proteins, protein aggregates, and organelles (such as mitochondria). Bcl-2 blocks this step by binding and inhibiting Beclin (more ...)
Autophagosomes have been observed by electron microscopy in mammalian cells since as early as the 1950s (68
), whereas the molecular era of autophagy study began little more than a decade ago, starting primarily from genetic screens in the budding yeast Saccharomyces cerevisiae
and the methylotrophic yeasts Pichia pastoris
and Hansenula polymorpha
, leading to the identification of 31 autophagy-related (ATG
) genes. The Atg proteins function at several physiologically continuous steps in autophagy (for instance, induction, cargo recognition and packaging, and vesicle formation and breakdown) and orchestrate much of the process. Many ATG
homologs have subsequently been identified and characterized in higher eukaryotes, suggesting that autophagy is a highly conserved pathway through evolution. In fungal cells, the site of autophagosome formation is termed the phagophore assembly site (PAS, also known as the preautophagosomal structure). This is the location where the phagophore, the initial sequestering structure, expands and the Atg proteins are recruited. Whereas in mammalian cells autophagosomes emerge from multiple sites, fungi appear to have one distinct PAS adjacent to the vacuole, which allows convenient studies of the mechanisms and dynamic stages of autophagosome biogenesis.
Although bulk cytosol can be randomly turned over through autophagy, in many cases autophagy displays substrate-specificity. For example, two yeast vacuolar proteases, α-mannosidase and the precursor form of aminopeptidase I [Ape1 (prApe1)], are synthesized in the cytoplasm and transported to the vacuole via a selective autophagy pathway, known as the cytoplasm-to-vacuole targeting (Cvt) pathway. The Cvt pathway is mechanistically and genetically similar to bulk autophagy, except that it occurs constitutively in normal growing conditions and in contrast to autophagy is biosynthetic (70
). In addition, ubiquitinated protein aggregates, and damaged or superfluous organelles are selectively targeted for degradation by autophagy. Different terms have been used to describe the selectivity of each process according to the cargo, such as autophagic degradation of mitochondria (mitophagy) (63
), ribosomes (ribophagy) (73
), peroxisomes (pexophagy) (25
), and endoplasmic reticulum (ER; reticulophagy) (5
). This review provides an overview of recent advances in our understanding of the regulation of different types of autophagy in response to various stimuli or inhibitors, involving signaling pathways, transcription factors, and protein modifiers, as well as functions and interactions of the Atg proteins.