Insight into p62 mediated condensation and cargoes recognition

Selective autophagy mediates the removal of harmful ubiquitinated proteins from the cytoplasm. Ubiquitinated proteins are clustered in a p62-dependent manner and are subsequently engulfed by autophagosomes to be delivered into lysosomes. However, the nature of the protein substrates targeted for autophagy is unclear. First, we developed a reconstituted system using purified components and showed that p62 and ubiquitinated proteins spontaneously coalesce into larger clusters and we demonstrated that efficient cluster formation is based on p62 filaments cross-linked by the ubiquitinated substrates. Second, to obtain insights into their composition, we developed a method to isolate p62 condensates and found that they are enriched in components of the translation machinery. Furthermore, p62 interacts with translation initiation factors and eIF2α and eIF4E are degraded by autophagy in a p62 dependent manner. These studies provided mechanistic insights on how substrates are channelled into autophagy and showed how p62-mediated autophagy may in part be linked to aberrant translation initiation.