斯坦福大学Judith Frydman团队宣布他们的最新研究提出了NAC通过隧道感应和伴侣作用控制新生链的命运。这一研究成果发表在2025年12月22日出版的国际学术期刊《自然》上。

研究团队发现NAC是一个多方面的调节因子，通过与核糖体出口通道内外的新生多肽的不同相互作用来协调翻译延伸、共翻译折叠和细胞器靶向。利用秀丽隐杆线虫的NAC选择性核糖体分析，研究团队确定了新生蛋白质组中序列特异性NAC结合事件的要求，揭示了细胞质、核、内质网和线粒体蛋白中疏水和螺旋基序的广泛共翻译作用。出乎意料的是，研究组发现了一种隧道内传感模式，其中NAC以序列特异性的方式在出口隧道内与具有极短新生多肽的核糖体接合。

此外，最初的NAC相互作用诱导早期延伸减缓，调节核糖体通量并防止核糖体碰撞，将NAC的伴侣活性与翻译的动力学控制联系起来。研究小组提出NAC作用通过屏蔽两亲螺旋来保护易于聚集的中间体，从而促进细胞核折叠。NAC还通过早期识别信号序列和跨膜结构域支持线粒体膜蛋白的生物发生和内质网靶向。他们的研究结果表明NAC是一个早期的、多方面的协同翻译蛋白静止的协调者，根据它们的序列特征和亚细胞目的地，在新生链上具有不同的作用机制。

据了解，新生多肽相关复合体（NAC）是一种保守的核糖体结合因子，在蛋白质生物发生中具有重要但尚未完全了解的作用。

附：英文原文

Title: NAC controls nascent chain fate through tunnel sensing and chaperone action

Author: Lee, Jae Ho, Rabl, Laurenz, Gamerdinger, Martin, Goyal, Vaishali, Khakzar, Katrin Michaela, Barbosa, Natalia Moreira, Abramovich, Juliana, Morales-Polanco, Fabian, Khler, Ann-Kathrin, Samatova, Ekaterina, Rodnina, Marina V., Deuerling, Elke, Frydman, Judith

Issue&Volume: 2025-12-22

Abstract: The nascent polypeptide-associated complex (NAC) is a conserved ribosome-bound factor with essential yet incompletely understood roles in protein biogenesis1. Here, we show that NAC is a multifaceted regulator that coordinates translation elongation, cotranslational folding, and organelle targeting through distinct interactions with nascent polypeptides both inside and outside the ribosome exit tunnel. Using NAC-selective ribosome profiling in C. elegans, we identify thousands of sequence-specific NAC binding events across the nascent proteome, revealing broad cotranslational engagement with hydrophobic and helical motifs in cytosolic, nuclear, ER, and mitochondrial proteins. Unexpectedly, we discover an intra-tunnel sensing mode, where NAC engages ribosomes with extremely short nascent polypeptides inside the exit tunnel in a sequence-specific manner. Moreover, initial NAC interactions induce an early elongation slowdown that tunes ribosome flux and prevent ribosome collisions, linking NAC’s chaperone activity to kinetic control of translation. We propose NAC action protects aggregation-prone intermediates by shielding amphipathic helices, thus promoting cytonuclear folding. NAC also supports mitochondrial membrane protein biogenesis and ER targeting by early recognition of signal sequences and transmembrane domain. Our findings establish NAC as an early-acting, multifaceted orchestrator of cotranslational proteostasis, with distinct mechanisms of action on nascent chains depending on their sequence features and subcellular destinations.

DOI: 10.1038/s41586-025-10058-2

Source: https://www.nature.com/articles/s41586-025-10058-2