Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
Clinical Translation Research Center, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
Nat Microbiol. 2019 Aug;4(8):1378-1388. doi: 10.1038/s41564-019-0436-3. Epub 2019 May 20.
Mycobacterium tuberculosis (Mtb)-derived components are usually recognized by pattern recognition receptors to initiate a cascade of innate immune responses. One striking characteristic of Mtb is their utilization of different type VII secretion systems to secrete numerous proteins across their hydrophobic and highly impermeable cell walls, but whether and how these Mtb-secreted proteins are sensed by host immune system remains largely unknown. Here, we report that MPT53 (Rv2878c), a secreted disulfide-bond-forming-like protein of Mtb, directly interacts with TGF-β-activated kinase 1 (TAK1) and activates TAK1 in a TLR2- or MyD88-independent manner. MPT53 induces disulfide bond formation at C on TAK1 to facilitate its interaction with TRAFs and TAB1, thus activating TAK1 to induce the expression of pro-inflammatory cytokines. Furthermore, MPT53 and its disulfide oxidoreductase activity is required for Mtb to induce the host inflammatory responses via TAK1. Our findings provide an alternative pathway for host signalling proteins to sense Mtb infection and may favour the improvement of current vaccination strategies.
结核分枝杆菌（Mtb）来源的成分通常被模式识别受体识别，从而引发一系列先天免疫反应。Mtb 的一个显著特点是它们利用不同类型的 VII 型分泌系统将许多蛋白质分泌到其疏水性和高不透性的细胞壁中，但宿主免疫系统是否以及如何感知这些 Mtb 分泌的蛋白质在很大程度上尚不清楚。在这里，我们报告说，Mtb 的一种分泌型二硫键形成样蛋白 MPT53（Rv2878c）直接与转化生长因子-β激活激酶 1（TAK1）相互作用，并以 TLR2 或 MyD88 非依赖性方式激活 TAK1。MPT53 在 C 上诱导 TAK1 形成二硫键，以促进其与 TRAFs 和 TAB1 的相互作用，从而激活 TAK1 诱导促炎细胞因子的表达。此外，MPT53 及其二硫键氧化还原酶活性是 Mtb 通过 TAK1 诱导宿主炎症反应所必需的。我们的发现为宿主信号蛋白感知 Mtb 感染提供了一种替代途径，并可能有利于改进当前的疫苗接种策略。
