Journal
EMBO JOURNAL
Volume 20, Issue 24, Pages 7209-7219Publisher
WILEY-BLACKWELL
DOI: 10.1093/emboj/20.24.7209
Keywords
LST8; mitochondria; RTG genes; WD40 repeat; yeast
Categories
Funding
- NCI NIH HHS [CA77811] Funding Source: Medline
- NIGMS NIH HHS [GM22525, R37 GM022525] Funding Source: Medline
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In cells with reduced mitochondrial function, RTG1, 2 and 3 are required for expression of genes involved in glutamate synthesis. Glutamate negatively regulates RTG-dependent gene expression upstream of Rtg2p, which, in turn, acts upstream of the bHLH/Zip transcription factors, Rtg1p and Rtg3p. Here we report that some mutations [lst8-(2-5)] in LST8, an essential gene encoding a seven WD40-repeat protein required for targeting of amino acid permeases (AAPs) to the plasma membrane, bypass the requirement for Rtg2p and abolish glutamate repression of RTG-dependent gene expression. The lst8-1 mutation, however, which reduces plasma membrane expression of AAP, cannot bypass the Rtg2p requirement, but still suppresses glutamate repression of RTG target gene expression. We show that Lst8p negatively regulates RTG gene function, acting at two sites, one upstream of Rtg2p, affecting glutamate repression of RTG-dependent gene expression through Ssy1p, an AAP-like sensor of external amino acids, and the other between Rtg2p and Rtg1p-Rtg3p. These data, together with genome-wide transcription profiling, reveal pathways regulated by glutamate, and provide insight into the regulation of cellular responses to mitochondrial dysfunction.
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