Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Science. 2020 Dec 18;370(6523). doi: 10.1126/science.abc9359. Epub 2020 Nov 12.
MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to direct widespread posttranscriptional gene repression. Although association with AGO typically protects miRNAs from nucleases, extensive pairing to some unusual target RNAs can trigger miRNA degradation. We found that this target-directed miRNA degradation (TDMD) required the ZSWIM8 Cullin-RING E3 ubiquitin ligase. This and other findings support 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.
微小 RNA（miRNA）与 Argonaute（AGO）蛋白结合，从而指导广泛的转录后基因沉默。虽然与 AGO 的结合通常可以保护 miRNA 免受核酸酶的影响，但与一些不寻常的靶 RNA 的广泛配对可能会触发 miRNA 的降解。我们发现，这种靶向 miRNA 降解（TDMD）需要 ZSWIM8 Cullin-RING E3 泛素连接酶。这一发现和其他发现支持了一种 TDMD 的机制模型，其中靶定向 AGO 的蛋白酶体途径的蛋白水解作用使 miRNA 暴露于降解中。此外，功能丧失研究表明，ZSWIM8 Cullin-RING 连接酶加速了哺乳动物、苍蝇和线虫细胞中许多 miRNA 的降解，从而指定了大多数短寿命 miRNA 的半衰期。这些结果阐明了 TDMD 的机制，并扩展了其在塑造双边动物 miRNA 水平中的推断作用。
