The C-Box Region of MAF1 Regulates Transcriptional Activity and Protein Stability.
The C-Box Region of MAF1 Regulates Transcriptional Activity and Protein Stability.
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DOI：
10.1016/j.jmb.2016.12.012
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发表时间：
2017-01-20
影响因子：
5.6
通讯作者：
Curran SP
中科院分区：
文献类型：
--
作者：
Pradhan A;Hammerquist AM;Khanna A;Curran SP
MAF1 是跨物种 RNA 聚合酶 (pol) III 和细胞内脂质稳态的保守负调节因子。在这里，我们证明 MAF1 C 盒区域对其活性有负向调节作用。秀丽隐杆线虫 mafr-1 截短 C 盒的突变保留了抑制 RNA pol III 靶标转录、减少脂质生物发生和降低生殖输出的能力。在人类细胞中，MAF1 的 C 盒缺失导致 MAF1 核定位增加，并增强对 ACC1 和 FASN 的抑制，但对 RNA pol III 靶标的抑制受损。令人惊讶的是，C 盒突变使 MAF1 对雷帕霉素不敏感，进一步确定了该区域的调节作用。两个 MAF1 物种 MAF1L 和 MAF1S 受 C 盒 YSY 基序调节，该基序突变时会改变物种化学计量和核 MAF1 的蛋白酶体依赖性周转。我们的结果揭示了 C-box 区域作为 MAF1 稳定性、活性和细胞应激反应的关键决定因素的作用。
MAF1 is a conserved negative regulator of RNA polymerase (pol) III and intracellular lipid homeostasis across species. Here, we show that the MAF1 C-box region negatively regulates its activity. Mutations in Caenorhabditis elegans mafr-1 that truncate the C-box retain the ability to inhibit the transcription of RNA pol III targets, reduce lipid biogenesis, and lower reproductive output. In human cells, C-box deletion of MAF1 leads to increased MAF1 nuclear localization and enhanced repression of ACC1 and FASN, but with impaired repression of RNA pol III targets. Surprisingly, C-box mutations render MAF1 insensitive to rapamycin, further defining a regulatory role for this region. Two MAF1 species, MAF1L and MAF1S, are regulated by the C-box YSY motif, which, when mutated, alters species stoichiometry and proteasome-dependent turnover of nuclear MAF1. Our results reveal a role for the C-box region as a critical determinant of MAF1 stability, activity, and response to cellular stress.