Autophagy-Independent Functions of the Autophagy Machinery

Abstract

Macroautophagy (herein referred to as autophagy) is an evolutionary ancient mechanism that culminates with the lysosomal degradation of superfluous or potentially dangerous cytosolic entities. Over the past 2 decades, the molecular mechanisms underlying several variants of autophagy have been characterized in detail. Accumulating evidence suggests that most, if not all, components of the molecular machinery for autophagy also mediate autophagy-independent functions. Here, we discuss emerging data on the non-autophagic functions of autophagy-relevant proteins.

Keywords: ATG5; BECN1; LC3-associated phagocytosis; proliferation; regulated cell death; vesicular trafficking.

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).

Figure 2

Molecular Interface between Autophagy and Membrane Biology Multiple components of the molecular machinery for autophagy mediate non-autophagic functions linked to the rearrangement and trafficking of intracellular membranes independently of bona fide autophagic responses. In this setting, different supramolecular entities can be assembled around components of the class III phosphatidylinositol 3-kinase complex that drives autophagy (A) to differentially regulate specific non-autophagic functions, including LC3-associated phagocytosis (C), endocytosis (C), melanogenesis (D), cytokinesis (E), and GA-to-ER transport (F). ER, endoplasmic reticulum; GA, Golgi apparatus; PI3P, phosphatidylinositol 3-phosphate.

Figure 3

Non-autophagic Functions of the Autophagy Apparatus A large number of autophagy-relevant proteins mediate non-autophagic effects related to membrane biology and other cellular functions. Interestingly, many of these proteins operate in early steps of bona fide autophagic responses (e.g., initiation, nucleation, and elongation). ER, endoplasmic reticulum; GA, Golgi apparatus; LAP, LC3-associated phagocytosis; PRR, pattern recognition receptor.