Variation in ubiquitin system genes creates substrate-specific effects on proteasomal protein degradation.
Variation in ubiquitin system genes creates substrate-specific effects on proteasomal protein degradation.
复制标题
DOI：
10.7554/elife.79570
复制
发表时间：
2022-10-11
期刊：
影响因子：
7.7
通讯作者：
Albert FW
中科院分区：
文献类型：
--
作者：
Collins MA;Mekonnen G;Albert FW
精确控制蛋白质降解对生命至关重要，但自然遗传变异如何影响这一关键过程在很大程度上尚不清楚。在这里，我们开发了一种统计上强大的图谱方法来描述基因变异如何通过泛素-蛋白酶体系统(UPS)影响蛋白质降解。利用酿酒酵母，我们系统地定位了遗传对N-末端规则的影响，N-末端规则是一种蛋白质N-末端氨基酸作为降解促进信号的UPS途径。在所有20个可能的N末端氨基酸中，我们确定了149个影响UPS活性的基因组基因座，其中许多具有途径或底物特异性效应。四个基因座的精细定位发现了四个泛素系统基因中每一个基因的多个因果变异，这些基因的产物处理(NTA1)、识别(UBR1和DOA10)和泛素化(UBC6)细胞蛋白。一个通过改变UBR1表达来调节UPS活性的顺式作用启动子变异体改变了36种蛋白质的丰度，而不影响相应mRNA转录本的水平。我们的结果揭示了UPS活性变异的复杂遗传基础。
Precise control of protein degradation is critical for life, yet how natural genetic variation affects this essential process is largely unknown. Here, we developed a statistically powerful mapping approach to characterize how genetic variation affects protein degradation by the ubiquitin-proteasome system (UPS). Using the yeast Saccharomyces cerevisiae, we systematically mapped genetic influences on the N-end rule, a UPS pathway in which protein N-terminal amino acids function as degradation-promoting signals. Across all 20 possible N-terminal amino acids, we identified 149 genomic loci that influence UPS activity, many of which had pathway- or substrate-specific effects. Fine-mapping of four loci identified multiple causal variants in each of four ubiquitin system genes whose products process (NTA1), recognize (UBR1 and DOA10), and ubiquitinate (UBC6) cellular proteins. A cis-acting promoter variant that modulates UPS activity by altering UBR1 expression alters the abundance of 36 proteins without affecting levels of the corresponding mRNA transcripts. Our results reveal a complex genetic basis of variation in UPS activity.