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哺乳动物 UPF3A 和 UPF3B 可以在不结合其外显子连接复合物的情况下独立激活无意义介导的 mRNA 降解。

Mammalian UPF3A and UPF3B can activate nonsense-mediated mRNA decay independently of their exon junction complex binding.

机构信息

Center for RNA Biology, The Ohio State University, Columbus, OH, USA.

Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA.

出版信息

EMBO J. 2022 May 16;41(10):e109202. doi: 10.15252/embj.2021109202. Epub 2022 Apr 22.

DOI:10.15252/embj.2021109202
PMID:35451102
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9108626/
Abstract

Nonsense-mediated mRNA decay (NMD) is governed by the three conserved factors-UPF1, UPF2, and UPF3. While all three are required for NMD in yeast, UPF3B is dispensable for NMD in mammals, and its paralog UPF3A is suggested to only weakly activate or even repress NMD due to its weaker binding to the exon junction complex (EJC). Here, we characterize the UPF3A/B-dependence of NMD in human cell lines deleted of one or both UPF3 paralogs. We show that in human colorectal cancer HCT116 cells, NMD can operate in a UPF3B-dependent and -independent manner. While UPF3A is almost dispensable for NMD in wild-type cells, it strongly activates NMD in cells lacking UPF3B. Notably, NMD remains partially active in cells lacking both UPF3 paralogs. Complementation studies in these cells show that EJC-binding domain of UPF3 paralogs is dispensable for NMD. Instead, the conserved "mid" domain of UPF3 paralogs is consequential for their NMD activity. Altogether, our results demonstrate that the mammalian UPF3 proteins play a more active role in NMD than simply bridging the EJC and the UPF complex.

摘要

无意义介导的 mRNA 降解 (NMD) 由三个保守因子 UPF1、UPF2 和 UPF3 调控。虽然这三个因子在酵母中都是 NMD 所必需的，但 UPF3B 在哺乳动物中对于 NMD 是可有可无的，并且由于其与外显子结合复合物 (EJC) 的结合较弱，其同源物 UPF3A 被认为仅能弱激活或甚至抑制 NMD。在这里，我们研究了在缺失一个或两个 UPF3 同源物的人类细胞系中 NMD 的 UPF3A/B 依赖性。我们表明，在人类结直肠癌细胞 HCT116 中，NMD 可以以 UPF3B 依赖和非依赖的方式进行。虽然 UPF3A 在野生型细胞中对于 NMD 几乎是可有可无的，但它在缺乏 UPF3B 的细胞中强烈激活 NMD。值得注意的是，在缺乏两个 UPF3 同源物的细胞中，NMD 仍然保持部分活性。在这些细胞中的互补研究表明，UPF3 同源物的 EJC 结合结构域对于 NMD 是可有可无的。相反，UPF3 同源物的保守“中间”结构域对于它们的 NMD 活性是至关重要的。总之，我们的结果表明，哺乳动物 UPF3 蛋白在 NMD 中发挥的作用比简单地桥接 EJC 和 UPF 复合物更为积极。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb04/9108626/a1fba8af3738/EMBJ-41-e109202-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb04/9108626/c116a1fbd745/EMBJ-41-e109202-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb04/9108626/4ecc171a3fe5/EMBJ-41-e109202-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb04/9108626/a9f8ff922021/EMBJ-41-e109202-g007.jpg
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