How Fragile We Are: Influence of Stimulator of Interferon Genes (STING) Variants on Pathogen Recognition and Immune Response Efficiency

The stimulator of interferon genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP in the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the molecular mechanisms of these variants opens perspectives for personalized medicine treatments against diseases such as viral infections, cancers, or autoinflammatory diseases. Through microsecond-scale molecular modeling simulations, contact analyses, and machine learning techniques, we reveal the dynamic behavior of four STING variants (wild type, G230A, R293Q, and G230A/R293Q) and rationalize the variability of efficiency observed experimentally. Our results show that the decrease in STING activity is linked to a stiffening of key structural elements of the binding cavity together with changes in the interaction patterns within the protein.

干扰素基因刺激因子（stimulator of interferon genes, STING）蛋白是人体免疫应答的核心基石。当胞质DNA存在时，其可被环鸟苷酸-腺苷酸（cGAMP）激活，进而诱导I型干扰素与炎性细胞因子的产生。在人类群体中存在多种STING变体，这些变体的活性差异显著，会直接影响宿主对抗感染的防御效率。阐明此类变体的分子机制，可为病毒性感染、癌症、自身炎症性疾病等疾病的个性化医疗方案提供全新视角。本研究通过微秒级分子建模模拟、接触分析及机器学习技术，揭示了四种STING变体（野生型、G230A、R293Q以及G230A/R293Q）的动态行为，并对实验中观测到的活性效率差异作出了合理解释。研究结果显示，STING活性的降低与结合口袋关键结构元件的刚性化，以及蛋白质内部相互作用模式的改变紧密相关。