Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway
| Autor: | Ai Yamamoto, James E. Rothman, M. Laura Cremona |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Huntingtin
Insulin Receptor Substrate Proteins Nerve Tissue Proteins Biology Article Cell Line Mice Phosphatidylinositol 3-Kinases Mutant protein Huntingtin Protein Autophagy Animals Insulin RNA Small Interfering Protein kinase B PI3K/AKT/mTOR pathway Research Articles Gene Expression Profiling Intracellular Signaling Peptides and Proteins Nuclear Proteins Proteins Cell Biology Phosphoproteins Cell biology Insulin receptor Mutation biology.protein Beclin-1 Signal transduction Apoptosis Regulatory Proteins Signal Transduction |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 0021-9525 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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