Secretory Autophagy and Its Relevance in Metabolic and Degenerative Disease

Abstract

Proteins to be secreted through so-called "conventional mechanisms" are characterized by the presence of an N-terminal peptide that is a leader or signal peptide, needed for access to the endoplasmic reticulum and the Golgi apparatus for further secretion. However, some relevant cytosolic proteins lack of this signal peptides and should be secreted by different unconventional or "non-canonical" processes. One form of this unconventional secretion was named secretory autophagy (SA) because it is specifically associated with the autophagy pathway. It is defined by ATG proteins that regulate the biogenesis of the autophagosome, its representative organelle. The canonical macroautophagy involves the fusion of the autophagosomes with lysosomes for content degradation, whereas the SA pathway bypasses this degradative process to allow the secretion. ATG5, as well as other factors involved in autophagy such as BCN1, are also activated as part of the secretory pathway. SA has been recognized as a new mechanism that is becoming of increasing relevance to explain the unconventional secretion of a series of cytosolic proteins that have critical biological importance. Also, SA may play a role in the release of aggregation-prone protein since it has been related to the autophagosome biogenesis machinery. SA requires the autophagic pathway and both, secretory autophagy and canonical degradative autophagy are at the same time, integrated and highly regulated processes that interact in ultimate cross-talking molecular mechanisms. The potential implications of alterations in SA, its cargos, pathways, and regulation in human diseases such as metabolic/aging pathological processes are predictable. Further research of SA as potential target of therapeutic intervention is deserved.

Keywords: ATG (autophagy-related) proteins; IL-1β; aggregate-prone proteins; macroautophagy; unconventional protein secretion.

Figure 1

Autophagy overview diagram flow. Autophagosome biogenesis is mediated by ULK1 activation. Here is shown that VMP1, a transmembrane protein, recruits PI3K complex on the ER surface. Then DFCP1 recognizes the PI3P subdomain on the omegasome structure. Besides, WIPI proteins recruit the ATG16-ATG5-ATG12 protein complex on the isolation membrane. In turn, the ATG16-ATG5-ATG12 complex mentioned above mediates LC3 lipidation on the membrane. The genesis of the autophagosome as a double membrane vesicle allows carrying its cargo to the lysosome where the cargo is eventually degraded in the resulting autolysosome as a final structure [reviewed in (15)]. ER, endoplasmic reticulum; PI3K, phosphatidylinositol 3-kinase; PI3P, phosphatidylinositol (3,4,5) triphosphate (PI3P); ULK1, Unc-51-like kinase 1; VMP1, Vacuole Membrane Protein 1; DFCP1, Double FYVE-containing protein 1 (omegasome marker); WIPI, WD40-repeat phosphoinositide-interacting protein (isolation membrane marker); LC3, Microtubule-associated proteins 1A/1B light chain 3B (vesicle maturation/cargo recognition); ATG12, Autophagy-related protein 12 (member of ATG12-ATG5-ATG16L involved in LC3 conjugation to autophagosome membrane); ATG5, autophagy-related protein 5; ATG16, autophagy-related protein 16.