A selective autophagy pathway for phase separated endocytic protein deposits

Abstract

Autophagy eliminates cytoplasmic content selected by autophagy receptors, which link cargoes to the membrane bound autophagosomal ubiquitin-like protein Atg8/LC3. Here, we discover a selective autophagy pathway for protein condensates formed by endocytic proteins. In this pathway, the endocytic yeast protein Ede1 functions as a selective autophagy receptor. Distinct domains within Ede1 bind Atg8 and mediate phase separation into condensates. Both properties are necessary for an Ede1-dependent autophagy pathway for endocytic proteins, which differs from regular endocytosis, does not involve other known selective autophagy receptors, but requires the core autophagy machinery. Cryo-electron tomography of Ede1-containing condensates - at the plasma membrane and in autophagic bodies - shows a phase-separated compartment at the beginning and end of the Ede1-mediated selective autophagy pathway. Our data suggest a model for autophagic degradation of membraneless compartments by the action of intrinsic autophagy receptors. HighlightsO_LIEde1 is a selective autophagy receptor for aberrant CME protein assemblies C_LIO_LIAberrant CME assemblies form by liquid-liquid phase separation C_LIO_LICore autophagy machinery and Ede1 are important for degradation of CME condensates C_LIO_LIUltrastrucural view of a LLPS compartment at the PM and within autophagic bodies C_LI