E3泛素连接酶机制指定靶向microRNA降解，这一成果由霍华德休斯医学院David P. Bartel团队经过不懈努力而取得。这一研究成果发表在2026年3月18日出版的国际学术期刊《自然》上。

MicroRNAs（miRNAs）与Argonaute （AGO）蛋白结合形成复合物，下调靶RNA，包括大多数人类基因的信使RNA。在每个复合体中，miRNA配对到目标RNA， AGO提供了效应功能，同时也保护miRNA免受细胞核酸酶的攻击。尽管研究人员对miRNA导向的基因调控了解甚多，但对miRNA本身是如何调控的了解甚少。调控miRNA的一种途径涉及被称为“触发”RNA的非常规靶标，它逆转了规范的调控逻辑，转而下调miRNAs。这种靶向miRNA降解（TDMD）被认为需要cullin-RING E3连接酶，因为它依赖于cullin蛋白CUL3和其他泛素化成分，包括BC-box蛋白ZSWIM8。ZSWIM8是小鼠围产期生存能力和大多数短寿命miRNA失稳所必需的，这表明tdmd具有重要的生物学意义。

生化和细胞实验证实，ZSWIM8-CUL3 E3连接酶的AGO结合和多泛素化是TDMD的关键调控步骤，从而定义了一个独特的cullin-RING E3连接酶类。低温电子显微镜分析显示，ZSWIM8识别不同的AGO和RNA构象，这些构象是由miRNA与触发器配对形成的。AGO泛素化的特异性是通过可推广的RNA-RNA、RNA-蛋白和蛋白-蛋白相互作用建立的。E3连接酶识别的底物特征不符合传统的降解，而是建立了一种双RNA因子认证机制，用于指定蛋白质泛素化底物。

附：英文原文

Title: The E3 ubiquitin ligase mechanism specifying targeted microRNA degradation

Author: Farnung, Jakob, Slobodyanyuk, Elena, Wang, Peter Y., Blodgett, Lianne W., Lin, Daniel H., von Gronau, Susanne, Schulman, Brenda A., Bartel, David P.

Issue&Volume: 2026-03-18

Abstract: MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to form complexes that down-regulate target RNAs, including messenger RNAs from most human genes1,2,3. Within each complex, the miRNA pairs to target RNAs, and AGO provides effector function while also protecting the miRNA from cellular nucleases2,3,4,5. Although much is known about miRNA-directed gene regulation, less is known about how miRNAs themselves are regulated. One pathway that regulates miRNAs involves unusual targets called ‘trigger’ RNAs, which reverse the canonical regulatory logic and instead down-regulate miRNAs6,7,8,9. This target-directed miRNA degradation (TDMD) is thought to require a cullin–RING E3 ligase because it depends on the cullin protein CUL3 and other ubiquitylation components, including the BC-box protein ZSWIM8 (refs.10,11). ZSWIM8 is required for murine perinatal viability and for destabilization of most short-lived miRNAs, which suggests biological importance of TDMD11,12,13. Here, biochemical and cellular assays establish AGO binding and polyubiquitylation by the ZSWIM8–CUL3 E3 ligase as the key regulatory steps of TDMD, and thereby define a unique cullin–RING E3 ligase class. Cryogenic electron microscopy analyses show ZSWIM8 recognizing distinct AGO and RNA conformations shaped by pairing of the miRNA to the trigger. Specificity of AGO ubiquitylation is established through generalizable RNA–RNA, RNA–protein and protein–protein interactions. The substrate features recognized by the E3 ligase do not conform to a conventional degron14,15 but instead establish a two-RNA-factor authentication mechanism for specifying a protein ubiquitylation substrate.

DOI: 10.1038/s41586-026-10232-0

Source: https://www.nature.com/articles/s41586-026-10232-0