Naughton Brigitte S, Devarkar Swapnil C, Todorow Vanessa, Mallik Sunanda, Oxendine Stacey, Junnarkar Sanjana, Ren Yuan, Berro Julien, Kirstein Janine, Xiong Yong, Schlieker Christian
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
National Institutes of Health Post-Bac Research Education Program for Biological & Biomedical Sciences, Yale University , New Haven, CT, USA.
J Cell Biol. 2025 Sep 1;224(9). doi: 10.1083/jcb.202505010. Epub 2025 Jul 15.
The ER relies on membrane-shaping proteins to maintain a continuous network of sheets and tubules that host distinct biological processes. How this intricate structure of the ER membrane system is maintained under conditions of mechanical strain is incompletely understood. NOMO is an ER-resident transmembrane protein that contributes to ER morphology and is highly expressed in striated muscle. In this study, we identify a critical interface between distal Ig domains that enables NOMO to maintain ER morphology and bear mechanical forces. By incorporating two independent tension sensors in the luminal domain of NOMO, we demonstrate that NOMO assemblies experience forces in the single piconewton range, with a significant contribution from the identified interface. These newly defined features are important-if not indispensable-for myogenesis, as interface mutations affecting mechanosensitivity fail to restore the essential role of NOMO during myogenesis in a C2C12 differentiation model. Moreover, NOMO depletion impairs nematode motility, underscoring a broader functional importance in muscle physiology.
内质网依靠膜塑形蛋白来维持由片层和小管组成的连续网络，这些片层和小管承载着不同的生物学过程。目前尚不完全清楚在机械应变条件下，内质网膜系统的这种复杂结构是如何维持的。NOMO是一种内质网驻留跨膜蛋白，它对内质网形态有贡献，并且在横纹肌中高度表达。在本研究中，我们确定了远端免疫球蛋白结构域之间的一个关键界面，该界面使NOMO能够维持内质网形态并承受机械力。通过在NOMO的腔内结构域中引入两个独立的张力传感器，我们证明NOMO组装体承受的力在单皮牛顿范围内，其中已确定的界面起了重要作用。这些新定义的特征对肌生成很重要——如果不是必不可少的话——因为影响机械敏感性的界面突变无法在C2C12分化模型中恢复NOMO在肌生成过程中的关键作用。此外，NOMO缺失会损害线虫的运动能力，这突出了其在肌肉生理学中更广泛的功能重要性。
