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首页> 外文期刊>Journal of Cellular Physiology >Isoform-Specific SCFFbw7 Ubiquitination Mediates Differential Regulation of PGC-1 alpha
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Isoform-Specific SCFFbw7 Ubiquitination Mediates Differential Regulation of PGC-1 alpha

机译：Isoform-Specific SCFFbw7泛素化调节微分调节pgc - 1

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摘要

The E3 ubiquitin ligase and tumor suppressor SCFFbw7 exists as three isoforms that govern the degradation of a host of critical cell regulators, including c-Myc, cyclin E, and PGC-1 alpha. Peroxisome proliferator activated receptor-gamma coactivator 1 alpha (PGC-1 alpha) is a transcriptional coactivator with broad effects on cellular energy metabolism. Cellular PGC-1 alpha levels are tightly controlled in a dynamic state by the balance of synthesis and rapid degradation via the ubiquitin-proteasome system. Isoform-specific functions of SCFFbw7 are yet to be determined. Here, we show that the E3 ubiquitin ligase, SCFFbw7, regulates cellular PGC-1 alpha levels via two independent, isoform-specific, mechanisms. The cytoplasmic isoform (SCFFbw7 beta) reduces cellular PGC-1 alpha levels via accelerated ubiquitin-proteasome degradation. In contrast, the nuclear isoform (SCFFbw7 alpha) increases cellular PGC-1 alpha levels and protein stability via inhibition of ubiquitin-proteasomal degradation. When nuclear Fbw7 alpha proteins are redirected to the cytoplasm, cellular PGC-1 alpha protein levels are reduced through accelerated ubiquitin-proteasomal degradation. We find that SCFFbw7 beta catalyzes high molecular weight PGC-1 alpha-ubiquitin conjugation, whereas SCFFbw7 alpha produces low molecular weight PGC-1 alpha-ubiquitin conjugates that are not effective degradation signals. Thus, selective ubiquitination by specific Fbw7 isoforms represents a novel mechanism that tightly regulates cellular PGC-1 alpha levels. Fbw7 isoforms mediate degradation of a host of regulatory proteins. The E3 ubiquitin ligase, Fbw7, mediates PGC-1 alpha levels via selective isoform-specific ubiquitination. Fbw7 beta reduces cellular PGC-1 alpha via ubiquitin-mediated degradation, whereas Fbw7a increases cellular PGC-1 alpha via ubiquitin-mediated stabilization. (C) 2014 Wiley Periodicals, Inc.
机译：E3泛素连接酶和肿瘤抑制SCFFbw7管理存在三个亚型退化的重要细胞监管机构,包括原癌基因、细胞周期素E, PGC-1α。receptor-gamma共激活剂1α(pgc - 1)是一个广泛的转录辅激活吗对细胞能量代谢的影响。严格控制在pgc - 1的水平动态的合成和平衡通过ubiquitin-proteasome快速退化系统。尚未确定。SCFFbw7泛素连接酶,调节细胞通过两个独立的pgc - 1的水平,isoform-specific,机制。同种型(SCFFbw7β)减少细胞PGC-1通过加速ubiquitin-proteasomeα水平退化。(SCFFbw7α)增加细胞pgc - 1通过抑制和蛋白质稳定的水平ubiquitin-proteasomal退化。Fbw7α蛋白重定向到细胞质、细胞pgc - 1蛋白的水平通过加速减少ubiquitin-proteasomal退化。SCFFbw7β催化高分子量PGC-1 alpha-ubiquitin接合,而SCFFbw7α生产低分子量PGC-1alpha-ubiquitin轭合物不有效降解的信号。泛素化由特定Fbw7亚型代表了一个新颖的机制调节细胞pgc - 1的水平。亚型调解的退化调节蛋白。通过选择性Fbw7,介导pgc - 1的水平isoform-specific泛素化。减少细胞pgc - 1通过ubiquitin-mediated退化,而Fbw7a增加细胞pgc - 1通过ubiquitin-mediated稳定。期刊、公司。

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