Non-autophagic roles of autophagy-related proteins

Abstract

Autophagy and autophagy-related processes are fundamentally important in human health and disease. These processes are viewed primarily as cellular degradative pathways that recycle macromolecules and dysfunctional or redundant organelles into amino acids, sugars and lipids, especially during starvation. However, the ubiquitin-like autophagy proteins and other components of the autophagic machinery additionally participate in cellular reprogramming. We highlight these non-autophagic roles of autophagy proteins with the aim of drawing attention to this growing, but unexplored, research topic. We focus on the non-autophagic functions of autophagy proteins in cell survival and apoptosis, modulation of cellular traffic, protein secretion, cell signalling, transcription, translation and membrane reorganization.

Figure 1

Steps in autophagy—initiation occurs by activation of the Atg1 complex (ULK complex I in mammals). In yeast, this complex includes Atg1, Atg13 and the Atg17–Atg29–Atg31 subcomplex. The mammalian Atg1 complex has the yeast Atg1 homologue, Unc-51-like kinases 1 or 2 (ULK1 or ULK2, respectively), the autophagy-related 13 homologue (ATG13), a molecule functionally similar to yeast Atg17, FIP200 (focal adhesion kinase (FAK)-family-interacting protein of 200 kDa) and Atg101 [72]. Nucleation is the step that recruits proteins and lipids for autophagosome biogenesis. It begins with the recruitment of Atg proteins, such as ATG14L and WD-repeat proteins interacting with phosphoinositides (WIPIs), to the PAS—a step requiring the activity of the class 3, PI3K complex, as well as phosphatidylinositol 3-phosphate. Membrane expansion and closure—during autophagosome formation, an isolation membrane expands from the PAS, either by direct flow of membranes from a source such as the endoplasmic reticulum (ER) or by vesicle fusion. The isolation membrane surrounds the cargo, and fusion of the growing edge of the isolation membrane completes autophagosome formation. The two UBL-conjugation systems (Atg8/LC3 and Atg12) are involved in vesicle expansion and closure, and SNAREs are also probably involved. After autophagosome formation, several Atg proteins are recycled in a process involving Atg9. Autophagosome and lysosome fusion—the autophagosome fuses with the lysosome (the vacuole in yeast) to form an autolysosome, in which the cytosolic cargos are degraded and recycled. This process also involves SNAREs. PAS, phagophore assembly site; SNARE, soluble NSF-attachment protein receptor; UBL, ubiquitin-like.

Figure 2

Summary of non-autophagic roles of autophagy proteins. See text for details. C. elegans, Caenorhabditis elegans; CARD, caspase recruitment domain; CoV, coronavirus; HCV, hepatitis C virus; IFN, interferon; MHV, mouse hepatitis virus; MNV, murine norovirus; P. pastoris, Pichia pastoris.

Suresh Subramani

Vivek Malhotra