title: p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy.
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.
authors.affiliation: Molecular Cancer Research Group, Department of Medical Biology, University of Tromsø, Tromsø, Norway.
authors.forename: Terje Høyvarde
authors.initials: TH
authors.lastname: Clausen
authors.forename: Trond
authors.initials: T
authors.lastname: Lamark
authors.forename: Pauline
authors.initials: P
authors.lastname: Isakson
authors.forename: Kim
authors.initials: K
authors.lastname: Finley
authors.forename: Kenneth Bowitz
authors.initials: KB
authors.lastname: Larsen
authors.forename: Andreas
authors.initials: A
authors.lastname: Brech
authors.forename: Aud
authors.initials: A
authors.lastname: Øvervatn
authors.forename: Harald
authors.initials: H
authors.lastname: Stenmark
authors.forename: Geir
authors.initials: G
authors.lastname: Bjørkøy
authors.forename: Anne
authors.initials: A
authors.lastname: Simonsen
authors.forename: Terje
authors.initials: T
authors.lastname: Johansen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071183:Autophagy-Related Proteins; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D018942:Macrolides / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D017510:Protein Folding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D057149:Ubiquitinated Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D018942:Macrolides; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D014157:Transcription Factors; D057149:Ubiquitinated Proteins; C499825:WDFY3 protein, human; C040929:bafilomycin A1