Molecular determinants of selective clearance of protein inclusions by autophagy

Esther Wong, Eloy Bejarano, Moumita Rakshit, Karen Lee, Hugo H. Hanson, Nava Zaarur, Greg R. Phillips, Michael Y. Sherman, Ana Maria Cuervo

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Protein quality control is essential for cellular survival. Failure to eliminate pathogenic proteins leads to their intracellular accumulation in the form of protein aggregates. Autophagy can recognize protein aggregates and degrade them in lysosomes. However, some aggregates escape the autophagic surveillance. Here we analyse the autophagic degradation of different types of aggregates of synphilin-1, a protein often found in pathogenic protein inclusions. We show that small synphilin-1 aggregates and large aggresomes are differentially targeted by constitutive and inducible autophagy. Furthermore, we identify a region in synphilin-1, necessary for its own basal and inducible aggrephagy and sufficient for the degradation of other pro-aggregating proteins. Although the presence of this peptide is sufficient for basal aggrephagy, inducible aggrephagy requires its ubiquitination, which diminishes protein mobility on the surface of the aggregate and favours the recruitment and assembly of the protein complexes required for autophagosome formation. Our study reveals different mechanisms for cells to cope with aggregate proteins via autophagy and supports the idea that autophagic susceptibility of prone-to-aggregate proteins may not depend on the nature of the aggregating proteins per se, but on their dynamic properties in the aggregate.

Original languageEnglish (US)
Article number1240
JournalNature communications
Volume3
DOIs
StatePublished - 2012

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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