Abstract
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
Substances
-
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