溶酶体和lunapark标记的ER连接形成的分泌体翻译，这一成果由Janelia研究校园Jennifer Lippincott-Schwartz团队经过不懈努力而取得。这一研究成果于2025年11月5日发表在国际顶尖学术期刊《自然》上。

通过活细胞单分子成像，该研究团队证明分泌组mRNA翻译优先定位于富含结构蛋白lunapark的内质网连接，并且靠近溶酶体。Lunapark耗散降低了溶酶体附近的核糖体密度和分泌组mRNAs的翻译效率，这一作用依赖于eIF2介导的起始，并被综合应激反应抑制剂ISRIB逆转。溶酶体相关的翻译进一步受到营养状态的调节：氨基酸剥夺增强了溶酶体近端翻译，而溶酶体pH中和抑制了它。这些发现确定了内质网连接蛋白和溶酶体活性协同模式分泌组mRNA翻译的机制，将内质网结构和营养感知与分泌蛋白和膜蛋白的产生联系起来。

据了解，内质网（ER）是一个高度互联的膜网络，是蛋白质合成和成熟的中心位点。ER相关转录物的一个重要子集，被称为分泌组mRNAs，编码分泌、管腔和整体膜蛋白，占人类蛋白质编码基因的近三分之一。与细胞质mRNAs不同，分泌组mRNAs经历共翻译易位，它们需要翻译和蛋白质插入之间的精确协调。这一过程的破坏，如通过改变延伸率，激活应激反应途径，阻碍细胞生长，提出了分泌组翻译是否在空间上有组织以确保保真度的问题。

附：英文原文

Title: Secretome translation shaped by lysosomes and lunapark-marked ER junctions

Author: Choi, Heejun, Liao, Ya-Cheng, Yoon, Young J., Grimm, Jonathan, Wang, Nan, Lavis, Luke D., Singer, Robert H., Lippincott-Schwartz, Jennifer

Issue&Volume: 2025-11-05

Abstract: The endoplasmic reticulum (ER) is a highly interconnected membrane network that serves as a central site for protein synthesis and maturation1. A crucial subset of ER-associated transcripts, termed secretome mRNAs, encode secretory, lumenal and integral membrane proteins, representing nearly one-third of human protein-coding genes1. Unlike cytosolic mRNAs, secretome mRNAs undergo co-translational translocation, and thus require precise coordination between translation and protein insertion2,3. Disruption of this process, such as through altered elongation rates4, activates stress response pathways that impede cellular growth, raising the question of whether secretome translation is spatially organized to ensure fidelity. Here, using live-cell single-molecule imaging, we demonstrate that secretome mRNA translation is preferentially localized to ER junctions that are enriched with the structural protein lunapark and in close proximity to lysosomes. Lunapark depletion reduced ribosome density and translation efficiency of secretome mRNAs near lysosomes, an effect that was dependent on eIF2-mediated initiation and was reversed by the integrated stress response inhibitor ISRIB. Lysosome-associated translation was further modulated by nutrient status: amino acid deprivation enhanced lysosome-proximal translation, whereas lysosomal pH neutralization suppressed it. These findings identify a mechanism by which ER junctional proteins and lysosomal activity cooperatively pattern secretome mRNA translation, linking ER architecture and nutrient sensing to the production of secretory and membrane proteins.

DOI: 10.1038/s41586-025-09718-0

Source: https://www.nature.com/articles/s41586-025-09718-0