Shiftless Is a Novel Member of the Ribosome Stress Surveillance Machinery That Has Evolved to Play a Role in Innate Immunity and Cancer Surveillance.
Shiftless Is a Novel Member of the Ribosome Stress Surveillance Machinery That Has Evolved to Play a Role in Innate Immunity and Cancer Surveillance.
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DOI：
10.3390/v15122296
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发表时间：
2023-11-23
期刊：
影响因子：
--
通讯作者：
Dinman JD
中科院分区：
文献类型：
--
作者：
Kelly JA;Dinman JD
分子生物学中一个长期存在的悖论集中在蛋白质合成的长度问题上，尽管许多测量表明核糖体自发地以排除其完全翻译mRNA的能力的速率移动阅读框架。Shiftless（SFL; C19 orf 66）最初被鉴定为编码抗病毒蛋白的干扰素应答基因，表明它是先天免疫应答的一部分。这种活性是由于其结合核糖体的能力，核糖体已被病毒序列元件编程以改变阅读框。奇怪的是，Shiftless在哺乳动物细胞中以低水平组成型表达。这项研究探讨了改变Shiftless稳态的影响，揭示了高等真核生物如何使用它来识别和去除自发移码的核糖体，解决了蛋白质长度的明显限制。数据还表明，Shiftless在核糖体相关质量控制程序中发挥着新的作用。提出了一种模型，其中SFL识别和逮捕移码核糖体，并根据SFL蛋白浓度，要么导致移码核糖体的去除，而留下完整的mRNA，或mRNA降解。我们建议，SFL被添加到越来越多的蛋白质参与surveilling翻译保真度和控制基因表达在高等真核生物的万神殿。
A longstanding paradox in molecular biology has centered on the question of how very long proteins are synthesized, despite numerous measurements indicating that ribosomes spontaneously shift reading frame at rates that should preclude their ability completely translate their mRNAs. Shiftless (SFL; C19orf66) was originally identified as an interferon responsive gene encoding an antiviral protein, indicating that it is part of the innate immune response. This activity is due to its ability to bind ribosomes that have been programmed by viral sequence elements to shift reading frame. Curiously, Shiftless is constitutively expressed at low levels in mammalian cells. This study examines the effects of altering Shiftless homeostasis, revealing how it may be used by higher eukaryotes to identify and remove spontaneously frameshifted ribosomes, resolving the apparent limitation on protein length. Data also indicate that Shiftless plays a novel role in the ribosome-associated quality control program. A model is proposed wherein SFL recognizes and arrests frameshifted ribosomes, and depending on SFL protein concentrations, either leads to removal of frameshifted ribosomes while leaving mRNAs intact, or to mRNA degradation. We propose that SFL be added to the growing pantheon of proteins involved in surveilling translational fidelity and controlling gene expression in higher eukaryotes.
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