Mycobacterium tuberculosis inhibits the NLRP3 inflammasome activation via its phosphokinase PknF.
Mycobacterium tuberculosis inhibits the NLRP3 inflammasome activation via its phosphokinase PknF.
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DOI：
10.1371/journal.ppat.1009712
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发表时间：
2021-07
期刊：
影响因子：
6.7
通讯作者：
Briken V
中科院分区：
文献类型：
--
作者：
Rastogi S;Ellinwood S;Augenstreich J;Mayer-Barber KD;Briken V
结核分枝杆菌(Mtb)通过干扰巨噬细胞的功能来逃避宿主的天然免疫。白介素1β(IL-1β)是巨噬细胞在激活炎性小体复合体后分泌的，对宿主抵抗结核分枝杆菌感染至关重要。我们先前已经证明Mtb能够抑制AIM2炎症小体的激活和随后的下垂。在这里，我们发现Mtb还能够抑制宿主细胞NLRP3炎性小体的激活和下垂。我们鉴定丝氨酸/苏氨酸激酶pKnF是Mtb中参与抑制NLRP3炎症体的蛋白之一，因为Mtb的pKnF缺失突变能诱导骨髓来源的巨噬细胞产生IL-1β。在基因缺陷的BMDM中进行的研究表明，IL-1β的增加依赖于NLRP3、适配蛋白Asc和蛋白水解酶Caspase-1。此外，与感染结核分枝杆菌的细胞相比，携带该突变体的BMDM可引起更多的下垂，而IL-6的产生与感染Mtb的细胞相比没有变化，这表明该突变不影响炎性小体激活的启动步骤。相反，激活步骤受到影响，因为钾离子外流、氯离子外流和活性氧的产生在Mtb突变株介导的炎性小体激活和随后的松下垂过程中起着重要作用。综上所述，我们揭示了MTB的丝氨酸/苏氨酸激酶PKNF通过抑制NLRP3炎症体在先天免疫逃避中发挥重要作用。结核分枝杆菌(Mtb)感染每年导致数百万人死亡，这种病原体高度适应其人类宿主。宿主细胞吞噬细胞摄取结核杆菌，但细菌能够操纵宿主细胞来提高自身的生存能力。在目前的研究中，我们发现了Mtb操纵宿主细胞和先天免疫逃避的一条新途径。我们发现，在结核分枝杆菌感染后，宿主细胞防御复合体-炎症体的激活是有限的。最重要的是，我们确定了一种细菌蛋白PnuF，它参与了炎症体的抑制。
Mycobacterium tuberculosis (Mtb) has evolved to evade host innate immunity by interfering with macrophage functions. Interleukin-1β (IL-1β) is secreted by macrophages after the activation of the inflammasome complex and is crucial for host defense against Mtb infections. We have previously shown that Mtb is able to inhibit activation of the AIM2 inflammasome and subsequent pyroptosis. Here we show that Mtb is also able to inhibit host cell NLRP3 inflammasome activation and pyroptosis. We identified the serine/threonine kinase PknF as one protein of Mtb involved in the NLRP3 inflammasome inhibition, since the pknF deletion mutant of Mtb induces increased production of IL-1β in bone marrow-derived macrophages (BMDMs). The increased production of IL-1β was dependent on NLRP3, the adaptor protein ASC and the protease caspase-1, as revealed by studies performed in gene-deficient BMDMs. Additionally, infection of BMDMs with the pknF deletion mutant resulted in increased pyroptosis, while the IL-6 production remained unchanged compared to Mtb-infected cells, suggesting that the mutant did not affect the priming step of inflammasome activation. In contrast, the activation step was affected since potassium efflux, chloride efflux and the generation of reactive oxygen species played a significant role in inflammasome activation and subsequent pyroptosis mediated by the Mtb pknF mutant strain. In conclusion, we reveal here that the serine/threonine kinase PknF of Mtb plays an important role in innate immune evasion through inhibition of the NLRP3 inflammasome. Mycobacterium tuberculosis (Mtb) infections are causing millions of deaths per year and the pathogen is highly adapted to its human host. Host cell phagocytes take up Mtb but the bacterium is capable of manipulating the host cell to enhance its own survival. In the current study we discover a novel pathway of host cell manipulation and innate immune evasion by Mtb. We show that the activation of a host cell defense complex, the inflammasome, is limited after Mtb infection. Most importantly, we identify a bacterial protein, PknF, that is involved in inflammasome inhibition.
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影响因子：
7.3
作者：
Amaral EP;Riteau N;Moayeri M;Maier N;Mayer-Barber KD;Pereira RM;Lage SL;Kubler A;Bishai WR;D'Império-Lima MR;Sher A;Andrade BB
通讯作者：
Andrade BB
影响因子：
8.7
作者：
Broz P;Monack DM
通讯作者：
Monack DM
影响因子：
6.4
作者：
Dutta NK;Bandyopadhyay N;Veeramani B;Lamichhane G;Karakousis PC;Bader JS
通讯作者：
Bader JS
DOI：
10.1073/pnas.1607769113
发表时间：
2016-07-12
影响因子：
11.1
作者：
Aglietti, Robin A.;Estevez, Alberto;Dueber, Erin C.
通讯作者：
Dueber, Erin C.
影响因子：
4.5
作者：
Beatty, WL;Rhoades, ER;Russell, DG
通讯作者：
Russell, DG