美国霍华德休斯医学研究所David P. Bartel组取得最新进展。他们发现ZSWIM8泛素连接酶介导靶标指导的miRNA降解（TDMD）。该研究于2020年11月12日发表于国际一流学术期刊《科学》杂志上。

他们发现这种TDMD需要ZSWIM8 Cullin-RING E3泛素连接酶。这一发现和其他发现表明并支持了TDMD的机理模型，在该模型中，通过泛素-蛋白酶体途径进行的Argonaute（AGO）靶标蛋白水解暴露了MicroRNA（miRNA）的降解。

此外，功能丢失研究表明ZSWIM8 Cullin-RING连接酶可加速哺乳动物、果蝇和线虫细胞中多种miRNA的降解，从而确定了大多数短寿命miRNA的半衰期。这些结果阐明了TDMD的机制，并扩展了其在塑造两栖动物中miRNA水平方面的确切功能。

据悉，MiRNA与AGO蛋白相关联，以指导广泛的转录后基因抑制。 尽管与AGO的结合通常可保护miRNA免受核酸酶的影响，但与某些非常规靶RNA的广泛配对可触发miRNA降解。

附：英文原文

Title: The ZSWIM8 ubiquitin ligase mediates target-directed microRNA degradation

Author: Charlie Y. Shi, Elena R. Kingston, Benjamin Kleaveland, Daniel H. Lin, Michael W. Stubna, David P. Bartel

Issue&Volume: 2020/11/12

Abstract: MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to direct widespread post-transcriptional gene repression. Although association with AGO typically protects miRNAs from nucleases, extensive pairing to some unusual target RNAs can trigger miRNA degradation. Here we found that this target-directed miRNA degradation (TDMD) required the ZSWIM8 Cullin-RING E3 ubiquitin ligase. This and other findings suggested and supported a mechanistic model of TDMD in which target-directed proteolysis of AGO by the ubiquitin–proteasome pathway exposes the miRNA for degradation. Moreover, loss-of-function studies indicated that the ZSWIM8 Cullin-RING ligase accelerates degradation of numerous miRNAs in cells of mammals, flies, and nematodes, thereby specifying the half-lives of most short-lived miRNAs. These results elucidate the mechanism of TDMD and expand its inferred role in shaping miRNA levels in bilaterian animals.

DOI: 10.1126/science.abc9359

Source: https://science.sciencemag.org/content/early/2020/11/11/science.abc9359