德国马克斯·普朗克生物化学研究所Elena Conti和Ingmar B. Schäfer共同合作，近期取得重要工作进展。他们研究提出，人类外泌体-核糖体超复合体介导mRNA衰变的结构基础。相关研究成果2024年10月9日在线发表于《自然》杂志上。

据介绍，翻译和mRNA衰变之间的相互作用在人类细胞中很普遍。在质量控制途径中，与翻译核糖体相关的mRNA的外切降解主要由细胞质外泌体介导，其中包括外切核糖核酸酶复合物EXO10和解旋酶复合物SKI238。解旋酶可以从核糖体中提取mRNA，并通过桥接因子HBS1L3（也称为SKI7）将其转移到外核糖核酸酶核心，但这种分子转移的机制尚不清楚。

研究人员揭示了人类EXO10如何被HBS1L3（SKI7）招募到活性核糖体结合的SKI238复合物中。研究人员发现，不是顺序的交接，而是发生了直接的物理耦合机制，最终形成了细胞质外泌体-核糖体超复合物。在活性衰变过程中捕获结构揭示了一条连续的路径，其中RNA底物从80S核糖体穿过SKI2解旋酶进入细胞质外泌体复合物的外核糖核酸酶活性位点。复合物的SKI3亚基直接与HBS1L3（SKI7）结合，也与40S亚基的表面结合，在碰撞的二体中建立识别平台。

因此，外泌体和核糖体在共翻译mRNA衰变中作为一个单一的结构和功能单元协同工作，在瞬态超复合物中协调它们的活动。

附：英文原文

Title: Structural basis of mRNA decay by the human exosome–ribosome supercomplex

Author: Kgel, Alexander, Keidel, Achim, Loukeri, Matina-Jasemi, Kuhn, Christopher C., Langer, Lukas M., Schfer, Ingmar B., Conti, Elena

Issue&Volume: 2024-10-09

Abstract: The interplay between translation and mRNA decay is widespread in human cells1,2,3. In quality-control pathways, exonucleolytic degradation of mRNA associated with translating ribosomes is mediated largely by the cytoplasmic exosome4,5,6,7,8,9, which includes the exoribonuclease complex EXO10 and the helicase complex SKI238 (refs. 10,11,12,13,14,15,16). The helicase can extract mRNA from the ribosome and is expected to transfer it to the exoribonuclease core through a bridging factor, HBS1L3 (also known as SKI7), but the mechanisms of this molecular handover remain unclear7,17,18. Here we reveal how human EXO10 is recruited by HBS1L3 (SKI7) to an active ribosome-bound SKI238 complex. We show that rather than a sequential handover, a direct physical coupling mechanism takes place, which culminates in the formation of a cytoplasmic exosome–ribosome supercomplex. Capturing the structure during active decay reveals a continuous path in which an RNA substrate threads from the 80S ribosome through the SKI2 helicase into the exoribonuclease active site of the cytoplasmic exosome complex. The SKI3 subunit of the complex directly binds to HBS1L3 (SKI7) and also engages a surface of the 40S subunit, establishing a recognition platform in collided disomes. Exosome and ribosome thus work together as a single structural and functional unit in co-translational mRNA decay, coordinating their activities in a transient supercomplex.

DOI: 10.1038/s41586-024-08015-6

Source: https://www.nature.com/articles/s41586-024-08015-6