GlycoRNA与硫酸肝素络合调控VEGF-A信号传导，这一成果由波士顿儿童医院Ryan A. Flynn研究小组经过不懈努力而取得。相关论文于2026年1月28日发表在《自然》杂志上。

在这里，课题组研究了一类新的阴离子细胞表面偶联物glycoRNAs和细胞表面RNA结合蛋白（csRBPs）的组织规则。利用基因组规模的基因敲除筛选，课题组研究人员发现硫酸肝素的生物合成，特别是硫酸肝素链的6-O-硫酸形式，对于糖RNA和csRBPs（细胞表面核糖核蛋白（csRNPs））的组装至关重要。在机制上，课题组发现这些细胞可以拮抗肝素硫酸盐介导的VEGF-A下游ERK信号的激活。小组证明VEGF-A165的硫酸肝素结合区域负责结合RNA，破坏这种相互作用增强ERK信号并损害体外和体内血管发育，并且在物种中是保守的。他们的研究揭示了一个以前未被识别的调节轴，csRNPs通过该轴负向调节由VEGF-A驱动的血管生成中的硫酸肝素介导的信号。

据悉，硫酸肝素蛋白聚糖（HSPGs）已被认为是多种含有阳离子肝素结合域的生长因子和细胞因子的关键质膜连接共受体。然而，HSPGs如何在细胞表面（特别是在细胞表面RNA的背景下）机械地介导信号传导，仍然知之甚少。在发育和疾病过程中，血管内皮生长因子（VEGF-A），一种硫酸肝素结合因子，调节内皮细胞生长和血管生成。内皮细胞介导的VEGF-A选择性结合和活性的调控模式主要集中在了解阴离子硫酸肝素链的选择性硫酸化。

附：英文原文

Title: GlycoRNA complexed with heparan sulfate regulates VEGF-A signalling

Author: Chai, Peiyuan, Kheiri, Sina, Kuo, Andrew, Shah, Jessica, Kageler, Lauren, Ge, Ruiqi, Perr, Jonathan, Porat, Jennifer, Lebedenko, Charlotta G., Dias, Joao M. L., Yankova, Eliza, Rai, Sandeep K., Watkins, Christopher P., Hristov, Petar, Tzelepis, Konstantinos, Hla, Timothy, Raman, Ritu, Calo, Eliezer, Esko, Jeffrey D., Flynn, Ryan A.

Issue&Volume: 2026-01-28

Abstract: Heparan sulfate proteoglycans (HSPGs) have been recognized as key plasma membrane-tethered co-receptors for a broad range of growth factors and cytokines containing cationic heparan-binding domains1,2. However, how HSPGs mechanistically mediate signalling at the cell surface—particularly in the context of cell surface RNA—remain poorly understood. During developmental and disease processes, vascular endothelial growth factor (VEGF-A), a heparan sulfate-binding factor, regulates endothelial cell growth and angiogenesis3. The regulatory paradigm for endothelial cell-mediated selectively of VEGF-A binding and activity has largely been focused on understanding the selective sulfation of the anionic heparan sulfate chains4,5,6,7,8. Here we examine the organizational rules of a new class of anionic cell surface conjugates, glycoRNAs9,10, and cell surface RNA-binding proteins (csRBPs11,12). Leveraging genome-scale knockout screens, we discovered that heparan sulfate biosynthesis and specifically the 6-O-sulfated forms of heparan sulfate chains are critical for the assembly of clusters of glycoRNAs and csRBPs (cell surface ribonucleoproteins (csRNPs)). Mechanistically, we show that these clusters antagonize heparan sulfate-mediated activation of ERK signalling downstream of VEGF-A. We demonstrate that the heparan sulfate-binding domain of VEGF-A165 is responsible for binding RNA, and that disrupting this interaction enhances ERK signalling and impairs vascular development both in vitro and in vivo and is conserved across species. Our study thus uncovers a previously unrecognized regulatory axis by which csRNPs negatively modulate heparan sulfate-mediated signalling in the context of angiogenesis driven by VEGF-A.

DOI: 10.1038/s41586-025-10052-8

Source: https://www.nature.com/articles/s41586-025-10052-8