Department of Medicine, 1 & Deutsches Zentrum Immuntherapie, University of Erlangen-Nürnberg, Kussmaul Campus for Medical Research, 91054 Erlangen, Germany.
Department of Immunology & Microbiology, University of Colorado Anschutz School of Medicine, Aurora, CO 80045, USA.
Trends Immunol. 2024 Aug;45(8):580-596. doi: 10.1016/j.it.2024.06.004. Epub 2024 Jul 26.
The guanine nucleotide exchange factor (GEF) VAV1, a previously 'undruggable' protein integral to T/B lymphocyte antigen-receptor signaling, promotes actin polymerization, immunological synapse formation, T cell activation and differentiation, and cytokine production. With the development of novel modalities for targeting proteins, we hypothesize that interventions targeting VAV1 will have therapeutic potential in T and T/B cell-mediated autoimmune and chronic inflammatory diseases. This opinion is supported by recent CRISPR-Cas9 studies showing VAV1 as a key positive regulator of T cell receptor (TCR) activation and cytokine production in primary human CD4 and CD8 T cells; data demonstrating that loss/suppression of VAV1 regulates autoimmunity and inflammation; and promising preclinical data from T and T/B cell-mediated disease models of arthritis and colitis showing the effectiveness of selective VAV1 targeting via protein degradation.
鸟嘌呤核苷酸交换因子（GEF）VAV1 是一种以前“不可成药”的蛋白，是 T/B 淋巴细胞抗原受体信号传导所必需的，它促进肌动蛋白聚合、免疫突触形成、T 细胞激活和分化以及细胞因子的产生。随着针对蛋白质的新型靶向方法的发展，我们假设针对 VAV1 的干预措施将在 T 和 T/B 细胞介导的自身免疫和慢性炎症性疾病中具有治疗潜力。最近的 CRISPR-Cas9 研究支持这一观点，该研究表明 VAV1 是原代人 CD4 和 CD8 T 细胞中 TCR 激活和细胞因子产生的关键正向调节剂；数据表明，VAV1 的缺失/抑制可调节自身免疫和炎症；以及来自关节炎和结肠炎的 T 和 T/B 细胞介导疾病模型的有前景的临床前数据表明，通过蛋白降解选择性靶向 VAV1 的有效性。
