MHC-I associated peptides (MAPs) play a central role in the elimination of virus-infected and neoplastic cells by CD8 T cells. However, accurately predicting the MAP repertoire remains difficult, because only a fraction of the transcriptome generates MAPs. In this study, we investigated whether codon arrangement (usage and placement) regulates MAP biogenesis. We developed an artificial neural network called Codon Arrangement MAP Predictor (CAMAP), predicting MAP presentation solely from mRNA sequences flanking the MAP-coding codons (MCCs), while excluding the MCC per se. CAMAP predictions were significantly more accurate when using original codon sequences than shuffled codon sequences which reflect amino acid usage. Furthermore, predictions were independent of mRNA expression and MAP binding affinity to MHC-I molecules and applied to several cell types and species. Combining MAP ligand scores, transcript expression level and CAMAP scores was particularly useful to increaser MAP prediction accuracy. Using an in vitro assay, we showed that varying the synonymous codons in the regions flanking the MCCs (without changing the amino acid sequence) resulted in significant modulation of MAP presentation at the cell surface. Taken together, our results demonstrate the role of codon arrangement in the regulation of MAP presentation and support integration of both translational and post-translational events in predictive algorithms to ameliorate modeling of the immunopeptidome.

中文翻译：

---

CAMAP：人工神经网络揭示了密码子排列在调节MHC-1肽呈递中的作用

MHC-1相关肽（MAPs）在CD8 T细胞消除病毒感染和赘生性细胞中起着核心作用。但是，准确预测MAP库仍然很困难，因为只有一部分转录组会生成MAP。在这项研究中，我们调查了密码子排列（使用和放置）是否调节MAP生物发生。我们开发了一个人工神经网络，称为密码子排列MAP预测器（CAMAP），仅从MAP编码密码子（MCC）侧翼的mRNA序列预测MAP呈现，而排除了MCC本身。使用原始密码子序列时，CAMAP预测比反映氨基酸使用情况的改组密码子序列准确得多。此外，预测独立于mRNA表达和MAP与MHC-1分子的结合亲和力，并应用于几种细胞类型和物种。结合MAP配体评分，转录表达水平和CAMAP评分对提高MAP预测准确性特别有用。使用体外测定法，我们显示出在MCC侧翼区域中改变同义密码子（不改变氨基酸序列）会导致细胞表面MAP呈递的显着调节。综上所述，我们的结果证明了密码子排列在MAP呈递调节中的作用，并支持预测算法中翻译事件和翻译后事件的整合，以改善免疫肽组的建模。转录本表达水平和CAMAP分数对提高MAP预测准确性特别有用。使用体外测定法，我们显示出在MCC侧翼区域中改变同义密码子（不改变氨基酸序列）会导致细胞表面MAP呈递的显着调节。综上所述，我们的结果证明了密码子排列在MAP呈递调节中的作用，并支持预测算法中翻译事件和翻译后事件的整合，以改善免疫肽组的建模。转录本表达水平和CAMAP分数对提高MAP预测准确性特别有用。使用体外测定法，我们显示出在MCC侧翼区域中改变同义密码子（不改变氨基酸序列）会导致细胞表面MAP呈递的显着调节。综上所述，我们的结果证明了密码子排列在MAP呈递调节中的作用，并支持预测算法中翻译事件和翻译后事件的整合，以改善免疫肽组的建模。