Opportunistic fungal infections have become one of the leading causes of death among immunocompromised patients, resulting in an estimated 1.5 million deaths each year worldwide. The molecular mechanisms that promote host defense against fungal infections remain elusive. Here, we find that Myosin IF (MYO1F), an unconventional myosin, promotes the expression of genes that are critical for antifungal innate immune signaling and proinflammatory responses. Mechanistically, MYO1F is required for dectin-induced α-tubulin acetylation, acting as an adaptor that recruits both the adaptor AP2A1 and α-tubulin N-acetyltransferase 1 to α-tubulin; in turn, these events control the membrane-to-cytoplasm trafficking of spleen tyrosine kinase and caspase recruitment domain-containing protein 9. Myo1f-deficient mice are more susceptible than their wild-type counterparts to the lethal sequelae of systemic infection with Candida albicans. Notably, administration of Sirt2 deacetylase inhibitors, namely AGK2, AK-1, or AK-7, significantly increases the dectin-induced expression of proinflammatory genes in mouse bone marrow–derived macrophages and microglia, thereby protecting mice from both systemic and central nervous system C. albicans infections. AGK2 also promotes proinflammatory gene expression in human peripheral blood mononuclear cells after Dectin stimulation. Taken together, our findings describe a key role for MYO1F in promoting antifungal immunity by regulating the acetylation of α-tubulin and microtubules, and our findings suggest that Sirt2 deacetylase inhibitors may be developed as potential drugs for the treatment of fungal infections.

机会性真菌感染已成为免疫功能低下患者死亡的主要原因之一，估计全世界每年有 150 万人死亡。促进宿主防御真菌感染的分子机制仍然难以捉摸。在这里，我们发现肌球蛋白 IF (MYO1F) 是一种非常规肌球蛋白，可促进对抗真菌先天免疫信号传导和促炎反应至关重要的基因的表达。机械地，MYO1F需要的Dectin-α诱导的微管蛋白乙酰化，作为一个适配器，新兵适配器AP2A1和α微管蛋白两者ñ -乙酰基转移酶1〜α微管蛋白; 反过来，这些事件控制了脾酪氨酸激酶和含有半胱天冬酶募集结构域的膜到细胞质的运输蛋白质 9 . Myo1f 缺陷小鼠比它们的野生型小鼠更容易受到白色念珠菌全身感染的致命后遗症的影响。值得注意的是，给予 Sirt2 去乙酰化酶抑制剂，即 AGK2、AK-1 或 AK-7，可显着增加 dectin 诱导的小鼠骨髓源巨噬细胞和小胶质细胞中促炎基因的表达，从而保护小鼠免受全身和中枢神经系统的侵害白色念珠菌感染。AGK2 还促进 Dectin 刺激后人外周血单核细胞中促炎基因的表达。总之，我们的研究结果描述了 MYO1F 通过调节 α-微管蛋白和微管的乙酰化在促进抗真菌免疫中的关键作用，我们的研究结果表明，Sirt2 脱乙酰酶抑制剂可能被开发为治疗真菌感染的潜在药物。