Autophagy and Protein Secretion

Autophagy – conventional for macroautophagy – is a major recycling strategy that ensures cellular homeostasis through the selective engulfment of cytoplasmic supramolecular cargos in double membrane vesicles and their rapid dispatch to the lysosome for digestion. As autophagy operates in the cytoplasm, its interference with secretory proteins, that is, proteins destined to the plasma membrane or the extracellular space, generally synthesized and routed within the endoplasmic reticulum (ER), has been relatively overlooked in the past. However, mounting evidence reveals that autophagy in fact heavily regulates protein secretion through diverse mechanisms. First, autophagy is closely involved in the unconventional secretion of leaderless proteins, a pool of proteins destined extracellularly, but lacking an ER-targeted leader sequence, and thus manufactured in the cytosol. Autophagy-related (ATG) genes now appear instrumental to the underlying pathways, hence the recently coined concept of secretory autophagy, or better ATG gene–dependent secretion. Indeed, ATG genes regulate unconventional protein secretion at multiple levels, ranging from intracellular inflammatory signaling, for example, through the control of mitochondrial health and inflammasome activity, to trafficking of leaderless proteins. Moreover, perhaps less expectedly, autophagy also participates in the control of conventional secretion, intersecting the secretory apparatus at multiple points, though with surprising differences among professional secretory cell types that disclose remarkable and unpredicted specificity. This review synopsizes the multiple mechanisms whereby autophagy interfaces with conventional and unconventional protein secretory pathways and discusses the relative teleology. Altogether, the diverse controls exerted on protein secretion broaden and deepen the homeostatic significance of autophagy within the cell.