期刊
ELIFE
卷 9, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.62307
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资金
- National Cancer Institute [P30 CA 008748]
- Damon Runyon Cancer Research Foundation [DRG 2234-15]
An inadequate supply of amino acids leads to accumulation of uncharged tRNAs, which can bind and activate GCN2 kinase to reduce translation. Here, we show that glutamine-specific tRNAs selectively become uncharged when extracellular amino acid availability is compromised. In contrast, all other tRNAs retain charging of their cognate amino acids in a manner that is dependent upon intact lysosomal function. In addition to GCN2 activation and reduced total translation, the reduced charging of tRNA(Gl)(n) in amino-acid-deprived cells also leads to specific depletion of proteins containing polyglutamine tracts including core-binding factor al, mediator subunit 12, transcriptional coactivator CBP and TATA-box binding protein. Treating amino-aciddeprived cells with exogenous glutamine or glutaminase inhibitors restores tRNA(Gl)(n) charging and the levels of polyglutamine-containing proteins. Together, these results demonstrate that the activation of GCN2 and the translation of polyglutamine-encoding transcripts serve as key sensors of glutamine availability in mammalian cells.
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