Several key molecular components participate in the initiation, execution and completion of autophagy. Autophagy inducers such as starvation modulate the inhibitory interaction of TORC1 with the ULK1/2 complex. Through phosphorylation of Ambra1, and maybe through other putative interactions, ULK1/2 complex (A) also regulates the activity of Beclin 1/ class III phosphatidylinositol 3-kinase (PI3K) complex (B). Beclin 1 interacts with several enhancing (blue) or inhibitory (grey) factors that modulate its binding to Vps34, the catalytic unit of the PI3K, whose lipid kinase activity is essential for autophagy. In addition to these two complexes, autophagosome formation requires the participation of two ubiquitin-like protein (Atg12 and Atg8/LC3) conjugation systems and two transmembrane proteins (Atg9 and VMP-1) (C). Whereas the roles of Atg9 and VMP-1 are currently not completely understood, both conjugation systems are essential for the biogenesis of the isolation membrane, also called ‘phagophore’. In addition, the Atg8/LC3 system is required for autophagosome transport and maturation, as well as for the selection of autophagic cargo. Fully mature autophagosomes can fuse with Rab7-positive late endosomes to form amphisomes. Finally, autophagosomes or amphisomes fuse their external membranes with those from acidic lysosomes to acquire hydrolytic activity, degrade their cargo and recycle essential biomolecules to the cytoplasm (D).

Selected signals that converge on ULK1/2 (A) and the Beclin 1 complex (B) are depicted. Note the multiple positive and negative feedback loops depicted in A. For details see text.

A summary of starvation-induced pro-autophagic signaling (A) is followed by a schematic overview of the signaling cascades involving sirtuin-1 and Foxo 3a (B), AMPK (C) and mTORC1 (D).

For details see text.

The mechanisms involved in autophagy induction by hypoxia or anoxia (A); increased oxidative damage (reactive oxygen species, ROS) (B); perturbation of the p53 system (C) or mitochondrial dysfunction D) are represented schematically.

A. Particular stress stimuli (e.g. oxidative damage, hypoxia or anoxia, nutrient starvation, ER stress) can elicit different responses that cooperate to achieve optimal cellular repair and adaptation. A diverse range of stressors activate interconnected cytoprotective mechanisms able to modulate autophagy at different levels, such as transcriptional reprogramming, protein modifications (phosphorylation, acetylation, etc.) or cell cycle modulation. B. Autophagy inhibition and stress. Autophagy impairment leads to the accumulation of damaged proteins and organelles, which in turn can elicit cellular stress. Moreover, disabled autophagy can increase the abundance of p62, resulting in an enhanced activity of NF-κB, which leads to enhanced inflammation. By contrast, p62 accumulation leads to the activation of Nrf2 transcription factor and in a consequent increase in the expression of stress response enzymes. C. Mutual exclusion between autophagy and apoptosis. Autophagy, as a cytoprotective pathway, eliminates potential sources of pro-apoptotic stimuli such as damaged mitochondria, thereby setting a higher threshold against apoptosis induction. By contrast, the apoptosis-associated activation of proteases such as calpain and caspase-3 may destroy autophagy-specific factors (Atg4D, Beclin 1 or Atg5), thereby suppressing autophagy.