The Deubiquitylase Ubp15 Couples Transcription to mRNA Export

The nuclear export of messenger RNAs (mRNAs) is intimately coupled to their synthesis. pre-mRNAs assemble into dynamic ribonucleoparticles as they are being transcribed, processed and exported. The role of ubiquitylation in this process is increasingly recognized as the ubiquitylation of many key players have been shown to affect mRNA nuclear export. While a few E3 ligases have been shown to regulate nuclear export, evidence for deubiquitylases is currently lacking. Here, we identified the deubiquitylase Ubp15 as a regulator of nuclear export in Saccharomyces cerevisiae. Ubp15 interacts both with RNA polymerase II and with the nuclear pore complex, and its deletion reverts the nuclear export defect of mutants of the E3 ligase Rsp5. The deletion of UBP15 leads to hyper-ubiquitylation of the main nuclear export receptor Mex67 and affects its association with THO, a complex coupling transcription to mRNA processing and involved in the recruitment of mRNA export factors to nascent transcripts. Collectively, our data support a role for Ubp15 in coupling transcription to mRNA export.信使RNA（mRNA）的核输出过程与其合成紧密耦联。前体mRNA（pre-mRNA）在转录、加工与输出的过程中，会组装为动态的核糖核蛋白颗粒（ribonucleoparticles）。泛素化（ubiquitylation）在该过程中的作用日益受到学界重视，已有研究证实多种关键蛋白的泛素化会影响mRNA的核输出。尽管已有少量E3连接酶被证实可调控核输出，但目前尚无去泛素化酶（deubiquitylase）参与该过程的相关证据。本研究在酿酒酵母（Saccharomyces cerevisiae）中鉴定得到去泛素化酶Ubp15作为核输出调控因子。Ubp15可同时与RNA聚合酶II（RNA polymerase II）及核孔复合物（nuclear pore complex）发生相互作用，其基因缺失可逆转E3连接酶Rsp5突变体的核输出缺陷。UBP15基因缺失会导致主要核输出受体Mex67发生过度泛素化，并影响其与THO复合物的结合；THO复合物可耦联转录与mRNA加工过程，并参与将mRNA输出因子招募至新生转录本中。综上，本研究数据支持Ubp15在耦联转录与mRNA核输出过程中发挥作用。