A role for the eukaryotic translation initiation factor eIF4E in maintaining the homeostasis of RNA polymerase II

Unlike in prokaryotes, transcription and translation are physically separated in eukaryotes by the nuclear envelope. The translation initiation factor eIF4E, has additional nuclear functions during pre-mRNA processing and export. Here, we identify a previously unrecognized function of eIF4E in remodeling RNA polymerase II. Acute depletion of eIF4E triggers rapid degradation of the largest and second-largest RNAP II subunits, Rpb1 and Rpb2, while other subunits are left unchanged. This effect appears to depend on eIF4E cap-binding activity as it is phenocopied by inhibition of mRNA capping. Mechanistically, this pathway is distinct from canonical RNAP II degradation routes, as it depends neither on ubiquitination by the Elongin-Cullin system nor extraction by Cdc48/VCP. Instead, our data implicates the E3 ligase Asr1, which recognizes Ser5/Ser7-hyperphosphorylated CTD of RNAP II. We propose that this mechanism evolved in eukaryotes as a safeguard to ensure that the flux of transcription is fine-tuned to that of translation.与原核生物不同，真核生物的转录与翻译过程因核被膜的存在而在空间上相互分离。翻译起始因子eIF4E（translation initiation factor eIF4E）在前体mRNA加工与输出过程中具备额外的核内功能。本研究首次揭示了eIF4E在重塑RNA聚合酶II（RNA polymerase II, RNAP II）中的此前未被认知的功能。急性耗竭eIF4E会快速降解RNAP II中最大和第二大的亚基Rpb1与Rpb2，而其余亚基的水平无明显变化。该效应似乎依赖于eIF4E的mRNA帽结合活性，因为抑制mRNA加帽过程可重现这一表型。从机制层面而言，该通路与经典的RNAP II降解途径截然不同：它既不依赖于Elongin-Cullin系统介导的泛素化，也不依赖于Cdc48/VCP复合物的提取作用。我们的数据表明E3泛素连接酶（E3 ligase）Asr1参与其中，其可识别RNAP II上Ser5/Ser7高度磷酸化的羧基末端结构域（carboxy-terminal domain, CTD）。我们推测，这一机制在真核生物中演化形成，作为一种保障机制，确保转录通量与翻译通量得以精细匹配。