Programmed ribosomal frameshifting during PLEKHM2 mRNA decoding generates a constitutively active proteoform that supports myocardial function

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-10-24 DOI:10.1126/sciadv.ady1742

Gary Loughran, Raffaella De Pace, Ningyu Ding, Jianchao Zhang, Irwin Jungreis, Gionmattia Carancini, Jonathan M. Mudge, Ji Wang, Manolis Kellis, John F. Atkins, Pavel V. Baranov, Andrew E. Firth, Xiaowei Li, Juan S. Bonifacino, Yousuf A. Khan

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引用次数: 0

Abstract

Programmed ribosomal frameshifting is a process where a proportion of ribosomes change their reading frame on an mRNA. While frameshifting is commonly used by viruses, very few phylogenetically conserved examples are known in nuclear encoded genes. Here, we report a +1 frameshifting event during decoding of the human gene PLEKHM2 that provides access to a second internally overlapping ORF. The new carboxyl-terminal domain of this frameshift protein forms an α helix, which relieves PLEKHM2 from autoinhibition and allows it to move to the tips of cells without activation by ARL8. Reintroducing both the canonically translated and frameshifted protein are necessary to restore normal contractile function of PLEKHM2 knockout cardiomyocytes, demonstrating the necessity of frameshifting for normal cardiac activity.

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在PLEKHM2 mRNA解码过程中，程序性核糖体移框产生一种支持心肌功能的组成活性蛋白

程序性核糖体移框是一种核糖体在mRNA上改变其阅读框的过程。虽然病毒通常使用移帧，但已知的核编码基因中很少有系统发育上保守的例子。在这里，我们报告了人类基因PLEKHM2解码过程中的+1帧移事件，该事件提供了对第二个内部重叠ORF的访问。这个移码蛋白的新的羧基末端结构域形成一个α螺旋，从而解除PLEKHM2的自抑制作用，并允许它在不被ARL8激活的情况下移动到细胞的尖端。重新引入正常翻译和移框蛋白对于恢复PLEKHM2敲除心肌细胞的正常收缩功能是必要的，这证明了移框对于正常心脏活动的必要性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.