美国东北大学Nikolai Slavov小组在研究中取得进展。他们提出了交替的RNA解码导致哺乳动物中稳定和丰富的蛋白质。该研究于2026年6月24日发表于国际一流学术期刊《自然》杂志上。

为了解决这个问题，研究小组分析了来自1000多个人类样本的深层蛋白质组学、转录组学和基因组数据，包括6种癌症类型和26种健康人体组织。这项全球分析鉴定了60,803个片段谱，对应于来自1,767个基因的蛋白质的8,746个独特置换，包括1,955个确定的定位位点。一些替换在样本中是共享的，而另一些则表现出很强的组织类型和癌症特异性。

值得注意的是，数百种蛋白质的交替翻译产物比标准翻译产物更丰富，这表明存在意义密码子重编码。重新编码的蛋白质包括转录因子、蛋白酶、信号蛋白和与神经变性相关的蛋白质。影响替代丰度的机制包括蛋白质稳定性、密码子频率、密码子-反密码子错配和RNA修饰。该课题组人员还描述了如何交替翻译的蛋白质形态比率在蛋白质结构域，组织类型和癌症之间变化。这些比率与gnomAD数据库中的内在无序区域和遗传多态性呈正相关，尽管多态性不能解释替换。交替翻译蛋白的序列、相对丰度和组织特异性在人和小鼠之间是保守的。这些结果证明了交替翻译对哺乳动物蛋白质组多样化的贡献及其与蛋白质稳定性、组织特异性蛋白质组和疾病的关联。

据介绍，氨基酸取代可能会大大改变蛋白质的稳定性和功能。然而，由交替翻译（偏离遗传密码）产生的替代的贡献是未知的。

附：英文原文

Title: Alternate RNA decoding results in stable and abundant proteins in mammals

Author: Tsour, Shira, Machn, Rainer, Leduc, Andrew, Widmer, Simon, Koo, Eunice, Guez, Jeremy, Karczewski, Konrad J., Slavov, Nikolai

Issue&Volume: 2026-06-24

Abstract: Amino acid substitutions may substantially alter protein stability and function1,2. However, the contribution of substitutions that arise from alternate translation (deviations from the genetic code) is unknown. Here to address this issue, we analysed deep proteomic, transcriptomic and genomic data from more than 1,000 human samples, including 6 cancer types and 26 healthy human tissues. This global analysis identified 60,803 fragmentation spectra corresponding to 8,746 unique substitutions in proteins derived from 1,767 genes, including 1,955 confidently localized sites. Some substitutions were shared across samples, whereas others exhibited strong tissue-type and cancer specificity. Notably, products of alternate translation were more abundant than their canonical counterparts for hundreds of proteins, which suggests that there is sense-codon recoding. Recoded proteins included transcription factors, proteases, signalling proteins and proteins associated with neurodegeneration. Mechanisms that contribute to substitution abundance included protein stability, codon frequency, codon–anticodon mismatches and RNA modifications. We also characterized how alternatively translated proteoform ratios vary across protein domains, tissue types and cancers. These ratios were positively associated with intrinsically disordered regions and genetic polymorphisms in the gnomAD database, although the polymorphisms could not account for the substitutions. The sequence, relative abundance and the tissue specificity of alternatively translated proteins were conserved between humans and mice. These results demonstrate the contribution of alternate translation to the diversification of mammalian proteomes and its association with protein stability, tissue-specific proteomes and disease.

DOI: 10.1038/s41586-026-10678-2

Source: https://www.nature.com/articles/s41586-026-10678-2