Receptor oligomerization guides pathway choice between proteasomal and autophagic degradation

Nature Cell Biology
Kefeng LuStefan Jentsch

Abstract

Abnormal or aggregated proteins have a strong cytotoxic potential and are causative for human disorders such as Alzheimer's, Parkinson's, Huntington's disease and amyotrophic lateral sclerosis. If not restored by molecular chaperones, abnormal proteins are typically degraded by proteasomes or eliminated by selective autophagy. The discovery that both pathways are initiated by substrate ubiquitylation but utilize different ubiquitin receptors incited a debate over how pathway choice is achieved. Here, we demonstrate in yeast that pathway choice is made after substrate ubiquitylation by competing ubiquitin receptors harbouring either proteasome- or autophagy-related protein 8 (Atg8/LC3)-binding modules. Proteasome pathway receptors bind ubiquitin moieties more efficiently, but autophagy receptors gain the upper hand following substrate aggregation and receptor bundling. Indeed, by using sets of modular artificial receptors harbouring identical ubiquitin-binding modules we found that proteasome/autophagy pathway choice is independent of the ubiquitin-binding properties of the receptors but largely determined by their oligomerization potentials. Our work thus suggests that proteasomal degradation and selective autophagy are two bra...Continue Reading

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