Mechanisms of Selective Autophagy

Abstract

Selective autophagy contributes to intracellular homeostasis by mediating the degradation of cytoplasmic material such as aggregated proteins, damaged or over-abundant organelles, and invading pathogens. The molecular machinery for selective autophagy must ensure efficient recognition and sequestration of the cargo within autophagosomes. Cargo specificity can be mediated by autophagic cargo receptors that specifically bind the cargo material and the autophagosomal membrane. Here we review the recent insights into the mechanisms that enable cargo receptors to confer selectivity and exclusivity to the autophagic process. We also discuss their different roles during starvation-induced and selective autophagy. We propose to classify autophagic events into cargo-independent and cargo-induced autophagosome formation events.

Keywords: Atg8; autophagosome; autophagy; cargo receptor; isolation membrane.

Graphical abstract

Fig. 1

Autophagy delivers cytoplasmic material to the lysosomal compartment for degradation. (1) Membrane donors including Atg9 vesicles nucleate an isolation membrane. (2) The isolation membrane expands and engulfs cytoplasmic cargo material including organelles and macromolecules. (3) The isolation membrane matures into a closed double-membrane autophagosome. (4) The outer autophagosomal membrane fuses with a lysosome (or the vacuole in yeast), leading to the degradation of the inner membrane and the cargo. (5) Components are recycled back into the cytoplasm.

Fig. 2

Autophagosome formation during starvation-induced and starvation-independent autophagy. (A) During starvation, autophagosome formation is likely triggered independently of any cargo. (1) Starvation-dependent TOR complex inhibition results in activation of the Atg1/ULK1 complex and hierarchical recruitment of the autophagic machinery (PI3Kc1 complex, WIPIs, Atg9 vesicles, Atg12- and Atg8-conjugation systems) to the site of autophagosome formation. (2) The autophagic machinery nucleates an isolation membrane independently of any bound cargo. (3) Atg8 proteins and cargo-bound cargo receptors are recruited to the PAS. (4) Atg8 becomes membrane attached by lipidation and cargo receptors selectively tether their cargo to the isolation membrane, but engulfment of random cytoplasmic material is not prevented. (5) The isolation membrane matures into a closed autophagosome containing both selective cargos and random material. (B) In non-starved cells, selective autophagosomes and Cvt vesicles are generated in a cargo-dependent manner. (1) Autophagic substrates display a high local concentration of ligands (ubiquitin chains or motifs such as the prApe1 propeptide). (2) Cargo receptors are recruited to the cargo site via high-affinity or high-avidity interactions with the concentrated ligands. (3) Scaffold proteins (i.e., Atg11) and the autophagic machinery are hierarchically recruited to the cargo site via interactions with cargo receptors and/or the cargo. (4) The autophagic machinery is locally activated and drives the nucleation of an isolation membrane in proximity of the cargo. (5) The isolation membrane elongates until a complete autophagosome is formed. High-avidity interactions between cargo receptors and membrane-tethered Atg8-family proteins mediate close apposition of the membrane and the cargo resulting in the exclusion of other cytoplasmic material.