Portioning organelles for autophagic clearance

The lysosomal/vacuolar clearance of portions of organelles including the endoplasmic reticulum (ER), mitochondria, the Golgi apparatus and the nucleus, organellophagy, is mediated by autophagy receptors anchored at the surface of their respective organelles. Organellophagy receptors are activated, induced or derepressed in response to stimuli such as nutrient or oxygen deprivation, accumulation of toxic or aged macromolecules, membrane depolarization, pathogen invasion, cell differentiation and many others. Their activation drives the portioning of the homing organelle, and the engagement of Atg8/LC3/GABARAP (LC3) proteins via LC3-interacting regions (LIRs) that results in autophagic clearance. In our latest work, we elaborate on the fact that all known mammalian and yeast organellophagy receptors expose their LIR embedded within intrinsically disordered regions (IDRs), i.e. cytoplasmic stretches of amino acids lacking a fixed three-dimensional structure. Our experiments reveal that the IDR modules of organellophagy receptors are interchangeable, required and sufficient to induce the fragmentation of the organelle that displays them at the limiting membrane, independent of LC3 engagement. LC3 engagement drives lysosomal delivery. Building on these findings, we propose harnessing practical and therapeutic potential of controlled organelle fragmentation and organellophagy through ORGAnelle TArgeting Chimeras (ORGATACs).