Inserm UMRS 1131, Institut de Génétique Moléculaire, Université de Paris, Hôpital St. Louis, F-75010 Paris, France.
ICCVS, University of Gdańsk, Science, ul. Wita Stwosza 63, 80-308 Gdańsk, Poland.
Nucleic Acids Res. 2022 Sep 23;50(17):10110-10122. doi: 10.1093/nar/gkac751.
Protein aggregates and abnormal proteins are toxic and associated with neurodegenerative diseases. There are several mechanisms to help cells get rid of aggregates but little is known on how cells prevent aggregate-prone proteins from being synthesised. The EBNA1 of the Epstein-Barr virus (EBV) evades the immune system by suppressing its own mRNA translation initiation in order to minimize the production of antigenic peptides for the major histocompatibility (MHC) class I pathway. Here we show that the emerging peptide of the disordered glycine-alanine repeat (GAr) within EBNA1 dislodges the nascent polypeptide-associated complex (NAC) from the ribosome. This results in the recruitment of nucleolin to the GAr-encoding mRNA and suppression of mRNA translation initiation in cis. Suppressing NAC alpha (NACA) expression prevents nucleolin from binding to the GAr mRNA and overcomes GAr-mediated translation inhibition. Taken together, these observations suggest that EBNA1 exploits a nascent protein quality control pathway to regulate its own rate of synthesis that is based on sensing the nascent GAr peptide by NAC followed by the recruitment of nucleolin to the GAr-encoding RNA sequence.
蛋白质聚集体和异常蛋白质是有毒的，并与神经退行性疾病有关。有几种机制可以帮助细胞清除聚集体，但对于细胞如何防止易于聚集的蛋白质被合成知之甚少。爱泼斯坦-巴尔病毒 (EBV) 的 EBNA1 通过抑制自身 mRNA 翻译起始来逃避免疫系统，以尽量减少主要组织相容性 (MHC) 类 I 途径的抗原肽产生。在这里，我们表明 EBNA1 中无序甘氨酸-丙氨酸重复 (GAr) 的新兴肽将新生多肽相关复合物 (NAC) 从核糖体上置换下来。这导致核仁蛋白被招募到 GAr 编码的 mRNA 上，并抑制顺式 mRNA 翻译起始。抑制 NACα (NACA) 的表达可防止核仁蛋白与 GAr mRNA 结合，并克服 GAr 介导的翻译抑制。总之，这些观察结果表明，EBNA1 利用新生蛋白质质量控制途径来调节自身的合成速度，该途径基于通过 NAC 感知新生 GAr 肽，然后将核仁蛋白募集到 GAr 编码的 RNA 序列。
