Autophagy regulation by phase separation, avidity, and wetting.

Autophagy enables cells to selectively degrade a wide range of macromolecules, and how this process achieves spatial precision within the densely packed cytosol is an active area of investigation. Recent advances suggest that phase separation provides a crucial organizational framework that converts autophagy into a spatiotemporally coordinated and self-organizing process. Biomolecular condensates formed by phase separation can create high-avidity binding platforms between autophagy receptors, scaffold proteins, and the cargo that stabilize transient molecular contacts. The formation of such condensates specifies the cargo and initiates autophagosome formation at defined cellular locations. Simultaneously, physical properties such as wetting govern how condensates interact with membranes, and thus influence engulfment efficiency. Viewing autophagy through the lens of condensate physics not only explains its molecular specificity but also highlights new therapeutic opportunities.