Mycobacterium tuberculosis PPE51 Inhibits Autophagy by Suppressing Toll-Like Receptor 2-Dependent Signaling.
Mycobacterium tuberculosis PPE51 Inhibits Autophagy by Suppressing Toll-Like Receptor 2-Dependent Signaling.
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作者：
自噬是哺乳动物细胞中普遍存在的一种动态平衡途径，在宿主免疫中起着重要作用。大量证据表明，结核分枝杆菌(Mtb)成功逃避免疫反应的能力部分是由于自噬途径的抑制。我们之前对Mtb转座子突变体的筛选发现，PPE51蛋白是一个重要的自噬抑制效应因子。我们发现，PPE51的表达，无论是通过感染细菌还是通过在宿主细胞中直接表达，都会抑制对强大的自噬诱导刺激的反应，并干扰细菌的吞噬作用。这种表型与细胞外信号调节激酶1/2(ERK1/2)的激活减少有关，ERK1/2是刺激自噬的信号通路的关键组成部分。多条证据表明，PPE51的作用归因于Toll样受体2(TLR2)的信号阻断，TLR2是一种已知参与ERK1/2激活和自噬的受体。与这些结果一致的是，与野生型Mtb相比，具有完整TLR2信号的小鼠对Mtb ppe51缺失突变体(Δ51)的毒力显著减弱，而感染TLR2缺失小鼠的小鼠则没有表现出这种减弱。感染Δ51的小鼠也表现出对结核分枝杆菌抗原的T细胞反应增加，并在感染的肺组织中自噬增加。综上所述，这些结果表明，TLR2在分枝杆菌感染过程中激活了相关的宿主免疫功能，然后Mtb通过PPE51抑制TLR2信号来逃避这一功能。除了先前发现的通过细菌细胞壁运输底物的功能外，我们的结果还证明了PPE51在逃避对结核分枝杆菌的固有免疫和获得性免疫方面的直接作用。
Autophagy is an ubiquitous homeostatic pathway in mammalian cells and plays a significant role in host immunity. Substantial evidence indicates that the ability of Mycobacterium tuberculosis (Mtb) to successfully evade immune responses is partially due to inhibition of autophagic pathways. Our previous screening of Mtb transposon mutants identified the PPE51 protein as an important autophagy-inhibiting effector. We found that expression of PPE51, either by infecting bacteria or by direct expression in host cells, suppressed responses to potent autophagy-inducing stimuli and interfered with bacterial phagocytosis. This phenotype was associated with reduced activation of extracellular signal-regulated kinase 1/2 (ERK1/2), a key component of signaling pathways that stimulate autophagy. Multiple lines of evidence demonstrated that the effects of PPE51 are attributable to signal blocking by Toll-like receptor 2 (TLR2), a receptor with known involvement of activation of ERK1/2 and autophagy. Consistent with these results, mice with intact TLR2 signaling showed striking virulence attenuation for an Mtb ppe51 deletion mutant (Δ51) compared to wild-type Mtb, whereas infection of TLR2-deficient mice showed no such attenuation. Mice infected with Δ51 also displayed increased T cell responses to Mtb antigens and increased autophagy in infected lung tissues. Together, these results suggest that TLR2 activates relevant host immune functions during mycobacterial infection, which Mtb then evades through suppression of TLR2 signaling by PPE51. In addition to its previously identified function transporting substrates across the bacterial cell wall, our results demonstrate a direct role of PPE51 for evasion of both innate and adaptive immunity to Mtb.
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结核分枝杆菌对抗原呈递的调节：Toll 样受体的作用。
DOI：
10.1038/nrmicro2321
发表时间：
2010-04
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.6
作者：
Baker, Jacob J.;Abramovitch, Robert B.
通讯作者：
Abramovitch, Robert B.
影响因子：
3.1
作者：
Fulton, SA;Reba, SM;Boom, WH
通讯作者：
Boom, WH
影响因子：
4.4
作者：
Haehnel, V;Schwarzfischer, L;Rehli, M
通讯作者：
Rehli, M
结核分枝杆菌表面蛋白招募泛素来触发宿主异体吞噬
影响因子：
16.6
作者：
Chai, Qiyao;Wang, Xudong;Liu, Cui Hua
通讯作者：
Liu, Cui Hua