弗朗西斯·克里克研究所Jernej Ule团队报道了凝析易感性蛋白通过其mRNAs的集体稳态。相关论文于2025年9月24日发表于国际顶尖学术期刊《自然》杂志上。

在这里，课题组报告了“间滞”，这是一种稳态机制，在这种机制中，RNA-蛋白质凝聚物中蛋白质浓度的增加诱导了它们自身mRNAs的隔离。静态间mRNA捕获的选择性依赖于遗传密码的结构和保守密码子偏倚，这确保了相似的多价RNA区域编码相似的低复杂性结构域。例如，富含精氨酸的混合电荷结构域（R-MCDs）倾向于由mRNAs中重复的富含嘌呤的序列编码。含有R-MCDs的蛋白质的积累增加了核斑点的内聚性，从而诱导了富含嘌呤的多价mRNAs的选择性捕获。多价区由特定的RNA结合蛋白结合，包括TRA2蛋白，这些蛋白在间隙时重新定位到斑点，以促进选择性mRNA捕获。CLK介导的TRA2蛋白磷酸化对抗其定位到斑点，从而调节间期。核斑点的凝聚特性充当了间期的传感器，这是一个集体负反馈回路，共同调节高剂量敏感基因的mRNAs，这些基因主要编码核凝聚易感蛋白。

研究人员表示，必须严格控制含有内在无序区域的蛋白质的浓度，以维持细胞内稳态。然而，与膜结合细胞器介导的途径相比，这些蛋白的集体控制机制（它们倾向于定位于无膜凝聚物）的了解较少。

附：英文原文

Title: Collective homeostasis of condensation-prone proteins via their mRNAs

Author: Faraway, Rupert, Costello Heaven, Neve, Digby, Holly, Kuret Hodnik, Klara, Rebselj, Jure, Wilkins, Oscar G., Chakrabarti, Anob M., Iosub, Ira A., Vadnjal, Nea, Dore, Rhys, Knez, Lea, Ameres, Stefan L., Plaschka, Clemens, Ule, Jernej

Issue&Volume: 2025-09-24

Abstract: The concentration of proteins containing intrinsically disordered regions must be tightly controlled to maintain cellular homeostasis1,2. However, mechanisms for collective control of these proteins, which tend to localize to membraneless condensates, are less understood than pathways mediated by membrane-bound organelles3,4. Here we report ‘interstasis’, a homeostatic mechanism in which increased concentration of proteins within RNA–protein condensates induces the sequestration of their own mRNAs. The selectivity of interstatic mRNA capture relies on the structure of the genetic code and conserved codon biases, which ensure that similar multivalent RNA regions encode similar low-complexity domains. For example, arginine-enriched mixed charge domains (R-MCDs) tend to be encoded by repetitive purine-rich sequences in mRNAs. Accumulation of proteins containing R-MCDs increases the cohesion of nuclear speckles, which induces selective capture of purine-rich multivalent mRNAs. The multivalent regions are bound by specific RNA-binding proteins, including TRA2 proteins, which relocalize to speckles upon interstasis to promote selective mRNA capture. CLK-mediated phosphorylation of TRA2 proteins counters their localization to speckles, thereby modulating interstasis. Thus, the condensation properties of nuclear speckles act as a sensor for interstasis, a collective negative-feedback loop that co-regulates mRNAs of highly dosage-sensitive genes, which primarily encode nuclear condensation-prone proteins.

DOI: 10.1038/s41586-025-09568-w

Source: https://www.nature.com/articles/s41586-025-09568-w