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Abstract：
Mycobacterium tuberculosis (Mtb) survival and virulence largely reside on its ability to manipulate the host immune response. We have previously shown that M. tuberculosis Raf kinase inhibitor protein (RKIP) Rv2140c regulates diverse phosphorylation events in M. smegmatis. However, its role during infection is unknown. In this report, we show that Rv2140c can mimic the mammalian RKIP function. Rv2140c inhibit the activation of extracellular signal-regulated kinase (ERK) and nuclear factor κB (NF-κB) via decreasing the phosphorylation capacity of upstream mediators MEK1, ERK1/2, and IKKα/β, thus leading to a reduction in pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. This effect can be reversed by RKIP inhibitor locostatin. Furthermore Rv2140c mediates apoptosis associated with activation of caspases cascades. This modulation enhances the intracellular survival of M. smegmatis within macrophage. We propose that Rv2140c is a multifunctional virulence factor and a promising novel anti-Tuberculosis drug target.
摘要：
结核分枝杆菌（Mtb）的存活和毒力很大程度上取决于其操纵宿主免疫反应的能力。我们先前已经证明结核分枝杆菌Raf激酶抑制剂蛋白(RKIP)Rv2140c调节耻垢分枝杆菌中的不同磷酸化事件。然而,它在感染过程中的作用是未知的。在这份报告中,我们证明Rv2140c可以模拟哺乳动物的RKIP功能。Rv2140c通过降低上游介质MEK1，ERK1/2和IKKα/β的磷酸化能力，抑制细胞外信号调节激酶（ERK）和核因子κB（NF-κB）的激活，从而导致促炎细胞因子IL-1β的减少，IL-6和TNF-α。这种作用可以通过RKIP抑制剂洛科汀逆转。此外,Rv2140c介导与半胱天冬酶级联激活相关的细胞凋亡。这种调节增强了巨噬细胞内耻垢分枝杆菌的细胞内存活。我们认为Rv2140c是一种多功能毒力因子，是一种有前途的新型抗结核药物靶标。
