The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy.
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.
Filimonenko
Maria
M
Centre for Cancer Biomedicine, University of Oslo, Department of Biochemistry, The Norwegian Radium Hospital, Oslo, Norway.
Isakson
Pauline
P
Finley
Kim D
KD
Anderson
Monique
M
Jeong
Hyun
H
Melia
Thomas J
TJ
Bartlett
Bryan J
BJ
Myers
Katherine M
KM
Birkeland
Hanne C G
HC
Lamark
Trond
T
Krainc
Dimitri
D
Brech
Andreas
A
Stenmark
Harald
H
Simonsen
Anne
A
Yamamoto
Ai
A
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*
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