Initial Steps in Mammalian Autophagosome Biogenesis

Abstract

During the last decade, autophagy has been pointed out as a central process in cellular homeostasis with the consequent implication in most cellular settings and human diseases pathology. At present, there is significant data available about molecular mechanisms that regulate autophagy. Nevertheless, autophagy pathway itself and its importance in different cellular aspects are still not completely clear. In this article, we are focused in four main aspects: (a) Induction of Autophagy: Autophagy is an evolutionarily conserved mechanism induced by nutrient starvation or lack of growth factors. In higher eukaryotes, autophagy is a cell response to stress which starts as a consequence of organelle damage, such as oxidative species and other stress conditions. (b) Initiation of Autophagy; The two major actors in this signaling process are mTOR and AMPK. These multitasking protein complexes are capable to summarize the whole environmental, nutritional, and energetic status of the cell and promote the autophagy induction by means of the ULK1-Complex, that is the first member in the autophagy initiation. (c) ULK1-Complex: This is a highly regulated complex responsible for the initiation of autophagosome formation. We review the post-transductional modifications of this complex, considering the targets of ULK1. (d)The mechanisms involved in autophagosome formation. In this section we discuss the main events that lead to the initial structures in autophagy. The BECN1-Complex with PI3K activity and the proper recognition of PI3P are one of these. Also, the transmembrane proteins, such as VMP1 and ATG9, are critically involved. The membrane origin and the cellular localization of autophagosome biogenesis will be also considered. Hence, in this article we present an overview of the current knowledge of the molecular mechanisms involved in the initial steps of mammalian cell autophagosome biogenesis.

Defective lysosome reformation during autophagy causes skeletal muscle disease

“…The serine/threonine kinase mTOR couples autophagy activation with lysosome repopulation. mTOR inhibition during autophagy stimulates autophagosome formation (9), and concurrently promotes de novo lysosome biogenesis via activation of MITF transcription factors TFEB and TFE3 (10)(11)(12). Nearly all proteins required for lysosome biogenesis are under the transcriptional control of TFEB, a master regulator of the lysosomal system (3).…”

Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy

“…The EGF-activated nutrient responsive kinase mTOR is able to reduce autophagic flux [36][37][38]. ULK1 (unc-51-like kinase 1) is one of the key components of autophagosome biogenesis [39]. Under nutrient-rich conditions, the mTORC1 (mechanistic target of rapamycin complex 1) phosphorylates ULK1 and Atg13 and leads to the formation of ULK-Atg13-FIP 200 complex to reduce the kinase activity of ULK1 [38,40,41].…”

Secretory Autophagy and Its Relevance in Metabolic and Degenerative Disease

“…Two signaling pathways are associated with autophagy induction: those involve mTOR and AMPK activation. These signaling pathways can sense the environmental, nutritional and energetic status of the cell and promote autophagy through the ULK1-complex, which is the first member of the core molecular machinery in the autophagosome biogenesis [reviewed in (15,16)]. In brief: Following ULK1 complex activation, the transmembrane protein VMP1 (17) recruits on the ER surface contact site (18) where the first structure in the autophagosome biogenesis, called omegasome, is formed.…”

“…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.…”