Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that poses threats to the public. M. tuberculosis survives in macrophages by escaping from immune surveillance and clearance, which exacerbates the bacterial proliferation. However, the molecular mechanisms of this immune escape have not yet been fully understood. Using multiple cell and mouse models, we found that microRNA-325-3p (miR-325-3p) is upregulated after M. tuberculosis infection and Mir325-deficient mice show resistance to M. tuberculosis. We demonstrated that miR-325-3p directly targets LNX1, an E3 ubiquitin ligase of NEK6, and that this hampers the proteasomal degradation of NEK6 in macrophages. The abnormal accumulation of NEK6 leads to the activation of STAT3 signaling, thus inhibiting the process of apoptosis and promoting the intracellular survival of M. tuberculosis. Our findings not only reveal a new immune escape pathway of M. tuberculosis but also may provide new insights into the development of therapeutic approaches for drug-resistant TB.

中文翻译：

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MicroRNA-325-3p通过NEK6积累靶向LNX1，促进结核分枝杆菌的免疫逃逸，从而促进抗凋亡STAT3信号传导。

结核病（TB）是由结核分枝杆菌引起的传染病，对公众构成威胁。结核分枝杆菌通过逃避免疫监视和清除而在巨噬细胞中生存，这加剧了细菌的增殖。但是，这种免疫逃逸的分子机制尚未完全了解。使用多种细胞和小鼠模型，我们发现结核分枝杆菌感染后microRNA-325-3p（miR-325-3p）被上调，而Mir325缺陷型小鼠表现出对结核分枝杆菌的抗性。我们证明了miR-325-3p直接靶向LNX1（NEK6的E3泛素连接酶），并阻碍了巨噬细胞中NEK6的蛋白酶体降解。NEK6的异常积累导致STAT3信号的激活，从而抑制细胞凋亡过程并促进结核分枝杆菌的细胞内存活。我们的发现不仅揭示了结核分枝杆菌的新的免疫逃逸途径，而且可能为耐药结核病治疗方法的发展提供新的见解。