Burkholderia pseudomallei interferes with host lipid metabolism via NR1D2-mediated PNPLA2/ATGL suppression to block autophagy-dependent inhibition of infection.
Burkholderia pseudomallei interferes with host lipid metabolism via NR1D2-mediated PNPLA2/ATGL suppression to block autophagy-dependent inhibition of infection.
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DOI：
10.1080/15548627.2020.1801270
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发表时间：
2021-08
期刊：
影响因子：
13.3
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Tang M;Hu Z;Rao C;Chen J;Yuan S;Zhang J;Mao C;Yan J;Xia Y;Zhang M;Yue J;Xiang Y;Xie J;Mao X;Li Q
假马利氏伯克霍尔德菌：引起人类高死亡率的类鼻疽病，已成为全球关注的公共卫生问题。近年来，感染驱动的脂滴积累与宿主-病原体相互作用的进展有关，并对其在传染病发病机制中的作用进行了研究。在这里，我们证明假假芽孢杆菌感染积极诱导人肺上皮细胞和巨噬细胞中脂滴数量和大小的时间依赖性增加。我们还发现假芽孢杆菌感染后脂滴积累与PNPLA2/ATGL （patatin like phospholipase domain containing 2）下调和脂噬抑制有关。功能上，脂滴积聚通过PNPLA2下调促进，抑制了大自噬/自噬通量，从而阻碍了肺上皮细胞对假假芽孢杆菌感染的自噬依赖性抑制。在机制上，我们进一步发现核受体NR1D2可能参与细胞暴露于假芽孢杆菌后PNPLA2的抑制。综上所述，我们的发现揭示了一种进化策略，即假假芽孢杆菌干扰宿主脂质代谢，以阻止自噬依赖性的感染抑制。本研究提出了类鼻疽病临床治疗的潜在靶点。缩写：3-MA: 3-甲基腺嘌呤；ACTB：肌动蛋白；ATG7：自噬相关7；B. pseudomallei：伪伯克霍尔德氏杆菌；CFU：菌落形成单位；DG:甘油二酯;FASN：脂肪酸合成酶；GFP：绿色荧光蛋白；LAMP1：溶酶体相关膜蛋白1；LC-MS/MS：液相色谱-串联质谱；LD：脂滴；MAP1LC3B/LC3B：微管相关蛋白1轻链3 β；MG:单甘油酯;MOI:感染多重性;mRFP：单体红色荧光蛋白；NR1D2：核受体1亚家族D组2成员；皮,感染后;PLIN2/ADRP: perilipin 2；PNPLA2/ATGL: pattern like phosplipase domain containing 2；拉伯:雷帕霉素;SQSTM1/p62: sequestosome 1；shRNA：短发夹RNA；TEM：透射电子显微镜；TG:甘油三酸酯
Burkholderia pseudomallei: which causes melioidosis with high mortality in humans, has become a global public health concern. Recently, infection-driven lipid droplet accumulation has been related to the progression of host-pathogen interactions, and its contribution to the pathogenesis of infectious disease has been investigated. Here, we demonstrated that B. pseudomallei infection actively induced a time-dependent increase in the number and size of lipid droplets in human lung epithelial cells and macrophages. We also found that lipid droplet accumulation following B. pseudomallei infection was associated with downregulation of PNPLA2/ATGL (patatin like phospholipase domain containing 2) and lipophagy inhibition. Functionally, lipid droplet accumulation, facilitated via PNPLA2 downregulation, inhibited macroautophagic/autophagic flux and, thus, hindered autophagy-dependent inhibition of B. pseudomallei infection in lung epithelial cells. Mechanistically, we further revealed that nuclear receptor NR1D2 might be involved in the suppression of PNPLA2 after cell exposure to B. pseudomallei. Taken together, our findings unraveled an evolutionary strategy, by which B. pseudomallei interferes with the host lipid metabolism, to block autophagy-dependent suppression of infection. This study proposes potential targets for clinical therapy of melioidosis. Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; ATG7: autophagy related 7; B. pseudomallei: Burkholderia pseudomallei; CFU: colony-forming unit; DG: diglyceride; FASN: fatty acid synthase; GFP: green fluorescent protein; LAMP1: lysosomal associated membrane protein 1; LC-MS/MS: liquid chromatography-tandem mass spectrometry; LD: lipid droplet; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MG: monoglyceride; MOI: multiplicity of infection; mRFP: monomeric red fluorescent protein; NR1D2: nuclear receptor subfamily 1 group D member 2; p.i., post-infection; PLIN2/ADRP: perilipin 2; PNPLA2/ATGL: patatin like phospholipase domain containing 2; Rapa: rapamycin; SQSTM1/p62: sequestosome 1; shRNA: short hairpin RNA; TEM: transmission electron microscopy; TG: triglyceride
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