Loughran Gary, De Pace Raffaella, Ding Ningyu, Zhang Jianchao, Jungreis Irwin, Carancini Gionmattia, Mudge Jonathan M, Wang Ji, Kellis Manolis, Atkins John F, Baranov Pavel V, Firth Andrew E, Li Xiaowei, Bonifacino Juan S, Khan Yousuf A
School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
bioRxiv. 2025 Jan 14:2024.08.30.610563. doi: 10.1101/2024.08.30.610563.
Programmed ribosomal frameshifting is a process where a proportion of ribosomes change their reading frame on an mRNA, rephasing the ribosome relative to the mRNA. While frameshifting is commonly employed by viruses, very few phylogenetically conserved examples are known in nuclear encoded genes and some of the evidence is controversial. Here we report a +1 frameshifting event during decoding of the human gene . This frameshifting occurs at the sequence UCC_UUU_CGG, which is conserved in vertebrates and is similar to an influenza virus sequence that frameshifts with similar efficiency. The new C-terminal domain generated by this frameshift forms an α-helix, which relieves PLEKHM2 from autoinhibition and allows it to move to the tips of cells association with kinesin-1 without requiring activation by ARL8. Reintroducing both the canonically-translated and frameshifted protein are necessary to restore normal contractile function of -knockout cardiomyocytes, demonstrating the necessity of frameshifting for normal cardiac activity.
程序性核糖体移码是一个过程，其中一部分核糖体在信使核糖核酸（mRNA）上改变其阅读框，使核糖体相对于mRNA重新定相。虽然移码在病毒中普遍存在，但在核编码基因中已知的系统发育保守例子非常少，而且一些证据存在争议。在这里，我们报告了人类基因解码过程中的一个+1移码事件。这种移码发生在序列UCC_UUU_CGG处，该序列在脊椎动物中保守，并且与具有相似移码效率的流感病毒序列相似。由这种移码产生的新的C末端结构域形成一个α螺旋，它解除了PLEKHM2的自抑制作用，并使其能够在不依赖ARL8激活的情况下移动到细胞末端与驱动蛋白-1结合。重新引入正常翻译的和移码后的蛋白质对于恢复敲除基因的心肌细胞的正常收缩功能是必要的，这证明了移码对于正常心脏活动的必要性。
