Autophagy receptors: Molecular basis of selective Autophagy

Removal of harmful protein aggregates, damaged organelles and microbes is mediated by autophagy, a process by which the cell sequesters cytosolic cargo and delivers it for degradation by the lysosome. While autophagy can sequester cytosolic material non‐specifically, for example as a response to starvation, there is ample evidence for selective autophagic degradation of various cellular structures, including protein aggregates, mitochondria and microbes. Characterization of the molecular mechanisms, which govern the specificity, has been made possible by the identification of ATG proteins that regulate nucleation and maturation of the autophagosome in yeast and mammals. The central question of selective autophagy is how a particular substrate can engage the autophagosomal machinery to mediate phagophore assembly at a specific cellular location? The involvement of Ub in selective autophagy is becoming more evident: analogous to the proteasome, where ubiquitinated cargo is delivered by Ub receptors, autophagic clearance of protein aggregates requires specific autophagy receptors. We have recently published data regarding the roles of the ubiquitin sensors p62 and NBR1 and the mitochondrial damage sensor Nix in selective autophagic clearance of protein aggregates and damaged mitochondria. Both of the clearance pathways are important in retaining cellular homeostasis. Failure to clear these, especially damaged mitochondria producing excess reactive oxygen species, can lead to the accumulation of damage and eventually tumourigenesis. Currently we are evaluating the roles of such proteins as well as novel adaptor proteins in both normal and cancer cells. We will also discuss the molecular details of an increasing set of autophagy receptors suitable for clearance of various types of cargo, ranging from protein aggregates to membrane‐bound organelles and microbes.