Abstract：
G-Protein Pathway Suppressor 2 (GPS2) is an inhibitor of non-proteolytic K63 ubiquitination mediated by the E2 ubiquitin-conjugating enzyme Ubc13. Previous studies have associated GPS2-mediated restriction of ubiquitination with the regulation of insulin signaling, inflammatory responses and mitochondria-nuclear communication across different tissues and cell types. However, a detailed understanding of the targets of GPS2/Ubc13 activity is lacking. Here, we have dissected the GPS2-regulated K63 ubiquitome in mouse embryonic fibroblasts and human breast cancer cells, unexpectedly finding an enrichment for proteins involved in RNA binding and translation on the outer mitochondrial membrane. Validation of selected targets of GPS2-mediated regulation, including the RNA-binding protein PABPC1 and translation factors RPS1, RACK1 and eIF3M, revealed a mitochondrial-specific strategy for regulating the translation of nuclear-encoded mitochondrial proteins via non-proteolytic ubiquitination. Removal of GPS2-mediated inhibition, either via genetic deletion or stress-induced nuclear translocation, promotes the import-coupled translation of selected mRNAs leading to the increased expression of an adaptive antioxidant program. In light of GPS2 role in nuclear-mitochondria communication, these findings reveal an exquisite regulatory network for modulating mitochondrial gene expression through spatially coordinated transcription and translation.
摘要：
G蛋白途径抑制因子2（GPS2）是由E2泛素缀合酶Ubc13介导的非蛋白水解K63泛素化的抑制剂。以前的研究已经将GPS2介导的泛素化限制与胰岛素信号调节联系起来，不同组织和细胞类型之间的炎症反应和线粒体-核通讯。然而,缺乏对GPS2/Ubc13活性靶标的详细了解。这里,我们已经解剖了小鼠胚胎成纤维细胞和人乳腺癌细胞中GPS2调节的K63泛素组，出乎意料地发现了参与RNA结合和翻译的蛋白质在线粒体外膜上的富集。验证选定的GPS2介导的调控靶标，包括RNA结合蛋白PABPC1和翻译因子RPS1，RACK1和eIF3M，揭示了通过非蛋白水解泛素化调节核编码线粒体蛋白翻译的线粒体特异性策略。去除GPS2介导的抑制作用，通过基因缺失或应激诱导的核易位，促进所选mRNA的导入偶联翻译，导致适应性抗氧化剂程序的表达增加。鉴于GPS2在核-线粒体通讯中的作用，这些发现揭示了通过空间协调转录和翻译调节线粒体基因表达的精细调控网络。
