title: The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy.
abstract: There is growing evidence that macroautophagic cargo is not limited to bulk cytosol in response to starvation and can occur selectively for substrates, including aggregated proteins. It remains unclear, however, whether starvation-induced and selective macroautophagy share identical adaptor molecules to capture their cargo. Here, we report that Alfy, a phosphatidylinositol 3-phosphate-binding protein, is central to the selective elimination of aggregated proteins. We report that the loss of Alfy inhibits the clearance of inclusions, with little to no effect on the starvation response. Alfy is recruited to intracellular inclusions and scaffolds a complex between p62(SQSTM1)-positive proteins and the autophagic effectors Atg5, Atg12, Atg16L, and LC3. Alfy overexpression leads to elimination of aggregates in an Atg5-dependent manner and, likewise, to protection in a neuronal and Drosophila model of polyglutamine toxicity. We propose that Alfy plays a key role in selective macroautophagy by bridging cargo to the molecular machinery that builds autophagosomes.
authors.affiliation: Centre for Cancer Biomedicine, University of Oslo, Department of Biochemistry, The Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Maria
authors.initials: M
authors.lastname: Filimonenko
authors.forename: Pauline
authors.initials: P
authors.lastname: Isakson
authors.forename: Kim D
authors.initials: KD
authors.lastname: Finley
authors.forename: Monique
authors.initials: M
authors.lastname: Anderson
authors.forename: Hyun
authors.initials: H
authors.lastname: Jeong
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Melia
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Bartlett
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Myers
authors.forename: Hanne C G
authors.initials: HC
authors.lastname: Birkeland
authors.forename: Trond
authors.initials: T
authors.lastname: Lamark
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
authors.forename: Andreas
authors.initials: A
authors.lastname: Brech
authors.forename: Harald
authors.initials: H
authors.lastname: Stenmark
authors.forename: Anne
authors.initials: A
authors.lastname: Simonsen
authors.forename: Ai
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001343:Autophagy / Q000502:physiology*; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D008565:Membrane Proteins; D018129:Phosphatidylinositol Phosphates; D011506:Proteins; D014157:Transcription Factors; C499825:WDFY3 protein, human; C055525:phosphatidylinositol 3-phosphate