p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy.
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.
Clausen
Terje Høyvarde
TH
Molecular Cancer Research Group, Department of Medical Biology, University of Tromsø, Tromsø, Norway.
Lamark
Trond
T
Isakson
Pauline
P
Finley
Kim
K
Larsen
Kenneth Bowitz
KB
Brech
Andreas
A
Øvervatn
Aud
A
Stenmark
Harald
H
Bjørkøy
Geir
G
Simonsen
Anne
A
Johansen
Terje
T
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
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