Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway.
Conditional mouse models of polyglutamine diseases, such as Huntington's disease (HD), have revealed that cells can clear accumulated pathogenic proteins if the continuous production of the mutant transgene is halted. Invariably, the clearance of the protein leads to regression of the disease symptoms in mice. In light of these findings, it is critical to determine the pathway responsible for alleviating this protein accumulation to define targets to fight these diseases. In a functional genetic screen of HD, we found that activation of insulin receptor substrate-2, which mediates the signaling cascades of insulin and insulin-like growth factor 1, leads to a macroautophagy-mediated clearance of the accumulated proteins. The macroautophagy is triggered despite activation of Akt, mammalian target of rapamycin (mTOR), and S6 kinase, but still requires proteins previously implicated in macroautophagy, such as Beclin1 and hVps34. These findings indicate that the accumulation of mutant protein can lead to mTOR-independent macroautophagy and that lysosome-mediated degradation of accumulated protein differs from degradation under conditions of starvation.
Yamamoto
Ai
A
The Judith P. Sulzberger Columbia Genome Center, Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA.
Cremona
M Laura
ML
Rothman
James E
JE
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D002460:Cell Line; D020869:Gene Expression Profiling; D000071058:Huntingtin Protein; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology; D011506:Proteins / Q000502:physiology; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases