PDF(Pubmed)
Abstract：
IGHMBP2 is a non-essential, superfamily 1 DNA/RNA helicase that is mutated in patients with rare neuromuscular diseases SMARD1 and CMT2S. IGHMBP2 is implicated in translational and transcriptional regulation via biochemical association with ribosomal proteins, pre-rRNA processing factors, and tRNA-related species. To uncover the cellular consequences of perturbing IGHMBP2, we generated full and partial IGHMBP2 deletion K562 cell lines. Using polysome profiling and a nascent protein synthesis assay, we found that IGHMBP2 deletion modestly reduces global translation. We performed Ribo-seq and RNA-seq and identified diverse gene expression changes due to IGHMBP2 deletion, including ATF4 upregulation. With recent studies showing the ISR can contribute to tRNA metabolism-linked neuropathies, we asked whether perturbing IGHMBP2 promotes ISR activation. We generated ATF4 reporter cell lines and found IGHMBP2 knockout cells demonstrate basal, chronic ISR activation. Our work expands upon the impact of IGHMBP2 in translation and elucidates molecular mechanisms that may link mutant IGHMBP2 to severe clinical phenotypes.
摘要：
IGHMBP2是非必需的，在罕见神经肌肉疾病SMARD1和CMT2S患者中突变的超家族1DNA/RNA解旋酶。IGHMBP2通过与核糖体蛋白的生化关联参与翻译和转录调控，前rRNA加工因子，和tRNA相关的物种。为了揭示干扰IGHMBP2的细胞后果,我们产生了完全和部分IGHMBP2缺失K562细胞系。使用多聚体分析和新生蛋白质合成测定，我们发现IGHMBP2缺失会适度减少全局翻译。我们进行了Ribo-seq和RNA-seq，并确定了由于IGHMBP2缺失导致的不同基因表达变化。包括ATF4上调。最近的研究表明ISR可以促进与tRNA代谢相关的神经病,我们询问干扰IGHMBP2是否促进ISR激活。我们产生了ATF4报告细胞系，发现IGHMBP2敲除细胞显示基础，慢性ISR激活。我们的工作扩展了IGHMBP2在翻译中的影响，并阐明了可能将突变IGHMBP2与严重临床表型联系起来的分子机制。
