p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy

Autophagy. 2010 Apr;6(3):330-44. doi: 10.4161/auto.6.3.11226. Epub 2010 Apr 11.


Accumulation of ubiquitinated proteins in cytoplasmic and/or nuclear inclusions is a hallmark of several diseases associated with premature cell death. SQSTM1/p62 is known to bind ubiquitinated substrates and aid their aggregation and degradation by macroautophagy. We show here that p62 is required to recruit the large phosphoinositide-binding protein ALFY to cytoplasmic p62 bodies generated upon amino acid starvation or puromycin-treatment. ALFY, as well as p62, is required for formation and autophagic degradation of cytoplasmic ubiquitin-positive inclusions. Moreover, both p62 and ALFY localize to nuclear promyleocytic leukemia (PML) bodies. The Drosophila p62 homologue Ref(2) P accumulates in ubiquitinated inclusions in the brain of flies carrying mutations in the ALFY homologue Blue cheese, demonstrating that ALFY is required for autophagic degradation of p62-associated ubiquitinated proteins in vivo. We conclude that p62 and ALFY interact to organize misfolded, ubiquitinated proteins into protein bodies that become degraded by autophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Autophagy / physiology*
  • Autophagy-Related Proteins
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / anatomy & histology
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Enzyme Inhibitors / metabolism
  • HeLa Cells
  • Humans
  • Inclusion Bodies / metabolism*
  • Macrolides / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Multiprotein Complexes / metabolism
  • Protein Folding
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sequestosome-1 Protein
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitinated Proteins / metabolism


  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Proteins
  • Drosophila Proteins
  • Enzyme Inhibitors
  • Macrolides
  • Membrane Proteins
  • Multiprotein Complexes
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Transcription Factors
  • Ubiquitinated Proteins
  • WDFY3 protein, human
  • bafilomycin A1