Recent in vitro reconstitution analyses have proven that the physical interaction between the exosome core and MTR4 helicase, which promotes the exosome activity, is maintained by either MPP6 or RRP6. However, knowledge regarding the function of MPP6 with respect to in vivo exosome activity remains scarce. Here, we demonstrate a facilitative function of MPP6 that composes a specific part of MTR4-dependent substrate decay by the human exosome. Using RNA polymerase II-transcribed poly(A)+ substrate accumulation as an indicator of a perturbed exosome, we found functional redundancy between RRP6 and MPP6 in the decay of these poly(A)+ transcripts. MTR4 binding to the exosome core via MPP6 was essential for MPP6 to exert its redundancy with RRP6. However, at least for the decay of our identified exosome substrates, MTR4 recruitment by MPP6 was not functionally equivalent to recruitment by RRP6. Genome-wide classification of substrates based on their sensitivity to each exosome component revealed that MPP6 deals with a specific range of substrates and highlights the importance of MTR4 for their decay. Considering recent findings of competitive binding to the exosome between auxiliary complexes, our results suggest that the MPP6-incorporated MTR4-exosome complex is one of the multiple alternative complexes rather than the prevailing one.

中文翻译：

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MPP6 刺激 RRP6 和 DIS3 降解人细胞核中特定的 MTR4 敏感底物子集

最近的体外重组分析证明，外泌体核心和促进外泌体活性的 MTR4 解旋酶之间的物理相互作用是由 MPP6 或 RRP6 维持的。然而，关于 MPP6 在体内外泌体活性方面的功能的知识仍然很少。在这里，我们展示了 MPP6 的促进功能，它构成了人类外泌体 MTR4 依赖性底物衰变的特定部分。使用 RNA 聚合酶 II 转录的 poly(A)+ 底物积累作为外泌体受干扰的指标，我们发现 RRP6 和 MPP6 在这些 poly(A)+ 转录物的衰变中存在功能冗余。MTR4 通过 MPP6 与外泌体核心结合对于 MPP6 发挥其与 RRP6 的冗余是必不可少的。然而，至少对于我们鉴定的外泌体底物的衰变，MPP6 招募的 MTR4 在功能上不等同于 RRP6 的招募。基于对每种外泌体成分的敏感性对底物进行全基因组分类揭示了 MPP6 处理特定范围的底物，并强调了 MTR4 对其衰变的重要性。考虑到辅助复合物与外泌体竞争性结合的最新发现，我们的研究结果表明，MPP6 并入的 MTR4-外泌体复合物是多种替代复合物之一，而不是占主导地位的复合物。