School of Pharmaceutical Sciences, Tsinghua University, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing, China.
School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
Cell Rep. 2022 May 31;39(9):110880. doi: 10.1016/j.celrep.2022.110880.
Cyclic 2',3'-GMP-AMP (cGAMP) binds to and activates stimulator of interferon genes (STING), which then induces interferons to drive immune responses against tumors and pathogens. Exogenous cGAMP produced by infected and malignant cells and synthetic cGAMP used in immunotherapy must traverse the cell membrane to activate STING in target cells. However, as an anionic hydrophilic molecule, cGAMP is not inherently membrane permeable. Here, we show that LL-37, a human host defense peptide, can function as a transporter of cGAMP. LL-37 specifically binds cGAMP and efficiently delivers cGAMP into target cells. cGAMP transferred by LL-37 activates robust interferon responses and host antiviral immunity in a STING-dependent manner. Furthermore, we report that LL-37 inducers vitamin D and sodium butyrate promote host immunity by enhancing endogenous LL-37 expression and its mediated cGAMP immune response. Collectively, our data uncover an essential role of LL-37 in innate immune activation and suggest new strategies for immunotherapy.
环二核苷酸 2',3'-GMP-AMP（cGAMP）与干扰素基因刺激物（STING）结合并激活后者，STING 继而诱导干扰素产生，从而引发针对肿瘤和病原体的免疫反应。感染和恶性细胞产生的外源性 cGAMP 和免疫疗法中使用的合成 cGAMP 必须穿过细胞膜才能在靶细胞中激活 STING。然而，由于 cGAMP 是带负电荷的亲水性分子，因此其本身不能穿透细胞膜。在这里，我们证明了人类宿主防御肽 LL-37 可以作为 cGAMP 的转运蛋白。LL-37 特异性结合 cGAMP，并有效地将 cGAMP 递送至靶细胞。LL-37 转运的 cGAMP 通过 STING 依赖性方式激活强烈的干扰素反应和宿主抗病毒免疫。此外，我们报告称，维生素 D 和丁酸钠等 LL-37 诱导剂通过增强内源性 LL-37 表达及其介导的 cGAMP 免疫反应来促进宿主免疫。总的来说，我们的数据揭示了 LL-37 在先天免疫激活中的重要作用，并为免疫疗法提供了新策略。
