Figure 1.

Degradative Autophagic Responses, Autophagy Blockade, and Non-autophagic Functions of Autophagy Machinery

(A) In physiological conditions, autophagosomes form (1) and successfully fuse with lysosomes (2) at baseline rates, underling the ability of autophagy to support normal cellular functions.

(B) In the presence of an autophagic stimulus such as nutrient deprivation, the rate of autophagosome formation (3), autophagosome-lysosome fusion, and lysosomal degradation increases (4), resulting in accelerated degradation of autophagic substrates.

(C) Autophagosomes also accumulate in the absence of an upstream autophagic stimulus (5) when lysosomal functions are inhibited (6), such as in the presence of lysosomotropic agents.

(D) Finally, the autophagosome compartment expands, driven by an upstream stimulus (7), when autophagosomal content is destined to secretion, either upon (8) or independent of (9) fusion with lysosomes in the absence of lysosomal degradation. Thus, widely employed assays only based on the maturation of LC3 not only are unable to determine whether an expansion of the autophagosomal compartment compared to baseline (A) reflects upstream autophagy activation coupled to efficient lysosomal degradation (B) or downstream inhibition of autophagosome-lysosome fusion or lysosomal acidification (C), but also they cannot identify situations in which activation of upstream autophagy-relevant signaling modules mediate non-autophagic effects (D).