Inhibition of low-density lipoprotein uptake by Helicobacter pylori virulence factor CagA
Inhibition of low-density lipoprotein uptake by Helicobacter pylori virulence factor CagA
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DOI：
10.1016/j.bbrc.2021.03.170
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发表时间：
2021-04-10
影响因子：
3.1
通讯作者：
Hamada, Fumihiko
中科院分区：
文献类型：
--
作者：
Ninomiya, Ryo;Kubo, Shuichi;Hamada, Fumihiko
幽门螺杆菌（H.幽门螺杆菌感染主要引起胃十二指肠疾病，包括慢性胃炎、消化性溃疡和胃癌。近年来的研究表明，H.幽门螺杆菌，特别是携带毒力因子CagA（细胞毒素相关基因A）的菌株，有助于非胃系统性疾病的发展，包括高胆固醇血症和动脉粥样硬化性心血管疾病。然而，这种关联的机制尚未确定。在这项研究中，我们使用果蝇进行了大规模的遗传筛选，并确定了一种新的CagA靶向低密度脂蛋白受体（LDLR），它有助于清除循环LDL。我们发现CagA通过其羧基末端区域与LDLR发生物理相互作用，并抑制LDLR介导的LDL进入细胞。由于已知LDL受体介导的LDL摄取不足会增加血浆LDL并加速动脉粥样硬化，我们的研究结果可能为CagA阳性H.幽门螺杆菌和高胆固醇血症导致动脉粥样硬化性心血管疾病。(c)2021爱思唯尔公司All rights reserved.
Helicobacter pylori (H. pylori) infection mainly causes gastroduodenal diseases, including chronic gastritis, peptic ulcer disease and gastric cancer. In recent years, several studies have demonstrated that infection with H. pylori, especially strains harboring the virulence factor CagA (cytotoxin-associated gene A), contribute to the development of non-gastric systemic diseases, including hypercholesterolemia and atherosclerotic cardiovascular diseases. However, mechanisms underlying this association has not been defined. In this study, we carried out a large-scale genetic screen using Drosophila and identified a novel CagA target low-density lipoprotein receptor (LDLR), which aids in the clearance of circulating LDL. We showed that CagA physically interacted with LDLR via its carboxy-terminal region and inhibited LDLRmediated LDL uptake into cells. Since deficiency of LDLR-mediated LDL uptake has been known to increase plasma LDL and accelerate atherosclerosis, our findings may provide a novel mechanism for the association between infection with CagA-positive H. pylori and hypercholesterolemia leading to atherosclerotic cardiovascular diseases.(c) 2021 Elsevier Inc. All rights reserved.