Abstract:
Selective autophagy eliminates protein aggregates, damaged organelles, and other large targets that otherwise accumulate and cause disease. A class of specialized autophagy receptor proteins can recognize targets as well as proteins attached to the autophagosome membrane. It has remained unknown whether receptors perform functions beyond tethering targets to pre-existing autophagosome precursors. Here, we show that receptors bound to their targets play an instructive role in autophagy initiation by activating the master regulator of autophagosome formation, Atg1 kinase. Specifically, we found that in fed yeast cells, Atg1 activity is controlled by constitutive protein aggregates and the specific receptor that recognizes them. Using a cell-free assay for monitoring Atg1 activation, we showed that a chain of binding interactions between receptor-bound aggregates, a scaffold protein, and the Atg1 kinase catalytic subcomplex cause Atg1 to become active and phosphorylate downstream Atg effector proteins. Damaged peroxisomes, which are also targeted by selective autophagy, also activated Atg1 in vitro, via a distinct receptor. These findings reveal a mechanism that couples target detection by receptors to the initiation of new autophagosomes by Atg1 and argue that the rate of autophagosome formation is precisely coordinated with target abundance.