A leptospiral AAA+ chaperone-Ntn peptidase complex, HslUV, contributes to the intracellular survival of Leptospira interrogans in hosts and the transmission of leptospirosis.
A leptospiral AAA+ chaperone-Ntn peptidase complex, HslUV, contributes to the intracellular survival of Leptospira interrogans in hosts and the transmission of leptospirosis.
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钩端螺旋体 AAA 加上分子伴侣 - Ntn 肽酶复合物 HslUV 有助于问号钩端螺旋体在宿主细胞内存活和钩端螺旋体病的传播
DOI：
10.1038/emi.2017.93
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发表时间：
2017-11-29
影响因子：
13.2
通讯作者：
Yan J
中科院分区：
文献类型：
--
作者：
Dong SL;Hu WL;Ge YM;Ojcius DM;Lin X;Yan J
钩端螺旋体病是由钩端螺旋体引起的一种全球性的人畜共患病，但在世界许多地区被认为是一种新发或再发的传染病。迄今为止，对钩端螺旋体的致病和传播机制仍知之甚少。由于真核生物和原核生物的蛋白质在不利的环境中会发生变性，而分子伴侣蛋白酶/肽酶复合物会降解这些有害的蛋白质，因此我们推测感染也可能引起钩端螺旋体蛋白质变性，并且钩端螺旋体的HslU和HslV蛋白质在不利的环境中会发生变性。问号螺旋体可以组成一种复合物来降解变性蛋白质，从而增强钩端螺旋体在宿主中的存活。在这里，我们表明，钩端螺旋体HslUV是一个ATP依赖的伴侣蛋白-肽酶复合物，含有ATP酶与各种细胞活性（AAA+）和N-末端亲核（Ntn）水解酶超家族结构域，分别水解酪蛋白和胰凝乳蛋白酶样底物，这种水解被苏氨酸蛋白酶抑制剂阻断。J774A.1巨噬细胞感染后，钩体变性蛋白侵袭体增多，而hslUV基因缺失突变体则积累了更多的侵袭体。钩端螺旋体蛋白质在核糖体结构、鞭毛组装、双组分信号系统和跨膜转运等方面具有重要作用。与野生型菌株相比，突变株体外感染细胞导致更多的死亡钩端螺旋体，更少的钩端螺旋体菌落形成单位和更低的生长能力，但也显示出更低的半致死剂量，减轻组织病理学损伤和减少肺，肝，肾，外周血和尿液中的钩端螺旋体负荷。因此，我们的研究结果证实，HslUV AAA+伴侣蛋白-Ntn肽酶复合物的L。问号线虫有助于钩端螺旋体在宿主体内存活并传播钩端螺旋体病。
Leptospirosis caused by Leptospira is a zoonotic disease of global importance but it is considered as an emerging or re-emerging infectious disease in many areas in the world. Until now, the mechanisms about pathogenesis and transmission of Leptospira remains poorly understood. As eukaryotic and prokaryotic proteins can be denatured in adverse environments and chaperone–protease/peptidase complexes degrade these harmful proteins, we speculate that infection may also cause leptospiral protein denaturation, and the HslU and HslV proteins of L. interrogans may compose a complex to degrade denatured proteins that enhances leptospiral survival in hosts. Here we show that leptospiral HslUV is an ATP-dependent chaperone–peptidase complex containing ATPase associated with various cellular activity (AAA+) and N-terminal nucleophile (Ntn) hydrolase superfamily domains, respectively, which hydrolyzed casein and chymotrypsin-like substrates, and this hydrolysis was blocked by threonine protease inhibitors. The infection of J774A.1 macrophages caused the increase of leptospiral denatured protein aggresomes, but more aggresomes accumulated in hslUV gene-deleted mutant. The abundant denatured leptospiral proteins are involved in ribosomal structure, flagellar assembly, two-component signaling systems and transmembrane transport. Compared to the wild-type strain, infection of cells in vitro with the mutant resulted in a higher number of dead leptospires, less leptospiral colony-forming units and lower growth ability, but also displayed a lower half lethal dose, attenuated histopathological injury and decreased leptospiral loading in lungs, liver, kidneys, peripheral blood and urine in hamsters. Therefore, our findings confirmed that HslUV AAA+ chaperone–Ntn peptidase complex of L. interrogans contributes to leptospiral survival in hosts and transmission of leptospirosis.
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影响因子：
3.8
作者：
Biggs HM;Hertz JT;Munishi OM;Galloway RL;Marks F;Saganda W;Maro VP;Crump JA
通讯作者：
Crump JA
影响因子：
4.8
作者：
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通讯作者：
Goldberg, AL
影响因子：
82.9
作者：
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通讯作者：
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影响因子：
5.8
作者：
Komi, Komi Koukoura;Ge, Yu-Mei;Yan, Jie
通讯作者：
Yan, Jie
影响因子：
30.3
作者：
Fang FC;Frawley ER;Tapscott T;Vázquez-Torres A
通讯作者：
Vázquez-Torres A