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TMEM16F may be a new therapeutic target for Alzheimer's disease

Neural Regeneration Research 2023年第3期18卷 643-651页

作者： Zhi-Qiang Cui Xiao-Ying Hu Tuo Yang Jing-Wei Guan Ying Gu Hui-Yuan Li Hui-Yu Zhang Qing-Huan Xiao Xiao-Hong Sun Department of Neurology The Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoning ProvinceChina Department of Ion Channel Pharmacology School of PharmacyChina Medical UniversityShenyangLiaoning ProvinceChina

TMEM16F is involved in many physiological processes such as blood coagulation,cell membrane fusion and bone mineralization.Activation of TMEM16F has been studied in various central nervous system diseases.High TMEM16F level has been also found to participate in microglial phagocytosis and transformation.Microglia-mediated neuroinflammation is a key factor in promoting the progression of Alzheimer’s disease.However,few studies have examined the effects of TMEM16F on neuroinflammation in Alzheimer’s disease.In this study,we established TMEM16F-knockdown AD model in vitro and in vivo to investigate the underlying regulatory mechanism about TMEM16F-mediated neuroinflammation in AD.We performed a Morris water maze test to evaluate the spatial memory ability of animals and detected markers for the microglia M1/M2 phenotype and NLRP3 inflammasome.Our results showed that TMEM16F was elevated in 9-month-old APP/PS1 mice.After TMEM16F knockdown in mice,spatial memory ability was improved,microglia polarization to the M2 phenotype was promoted,NLRP3 inflammasome activation was inhibited,cell apoptosis and Aβplaque deposition in brain tissue were reduced,and brain injury was alleviated.We used amyloid-beta(Aβ_(25-35))to stimulate human microglia to construct microglia models of Alzheimer’s disease.The levels of TMEM16F,inducible nitric oxide synthase(iNOS),proinflammatory cytokines and NLRP3 inflammasome-associated biomarkers were higher in Aβ_(25-35) treated group compared with that in the control group.TMEM16F knockdown enhanced the expression of the M2 phenotype biomarkers Arg1 and Socs3,reduced the release of proinflammatory factors interleukin-1,interleukin-6 and tumor necrosis factor-α,and inhibited NLRP3 inflammasome activation through reducing downstream proinflammatory factors interleukin-1βand interleukin-18.This inhibitory effect of TMEM16F knockdown on M1 microglia was partially reversed by the NLRP3 agonist Nigericin.Our findings suggest that TMEM16F participates in neuroinflammation in Alzheimer’s disease throu

关键词： Alzheimer’s disease Aβplaque inflammatory cytokines M1 phenotype M2 phenotype microglia polarization neuroinflammation NLRP3 inflammasome siRNA TMEM16F

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TMEM16F通过内质网应激相关的PERK通路促进乳腺癌细胞的增殖和迁移

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作者：张璐中国医科大学

学位级别：硕士

目的:乳腺癌目前处于威胁女性健康的恶性肿瘤首位。多项报道表明乳腺癌中的内质网应激反应被激活。tmem16家族与肿瘤间有着密切关系,TMEM16F是tmem16家族的成员之一。且在前期的研究中发现TMEM16F在乳腺癌细胞质膜上和细胞内都有较高水... 详细信息

目的:乳腺癌目前处于威胁女性健康的恶性肿瘤首位。多项报道表明乳腺癌中的内质网应激反应被激活。tmem16家族与肿瘤间有着密切关系,TMEM16F是tmem16家族的成员之一。且在前期的研究中发现TMEM16F在乳腺癌细胞质膜上和细胞内都有较高水平表达,且与细胞增殖、迁移能力相关。本研究旨在探索TMEM16F是否通过内质网应激信号通路促进乳腺癌的发生发展。方法:在乳腺癌MCf-7和T47D细胞中,通过Western blot技术检测转染了过表达TMEM16F载体和TMEM16F sh RNA载体后细胞的GRP78,PERK,p-PERK,ATf4,IRE1,p-IRE1和ATf6的表达水平。应用CCK-8实验检测转染过表达TMEM16F载体和空载体后MCf-7和T47D细胞的增殖情况,同时检测应用BAPTA-AM和EGTA处理后的上述细胞的增殖情况。应用细胞划痕实验检测转染了过表达TMEM16F载体和TMEM16Fsh RNA载体的细胞迁移能力。此外,在转染了过表达TMEM16F载体的MCf-7和T47D细胞中,通过CCK-8实验和细胞划痕实验比较使用PERK抑制剂(GSK2606414)处理与未使用PERK抑制剂处理的细胞增殖和迁移能力差异。结果:1、在乳腺癌细胞MCf-7和T47D中,内质网应激的关键蛋白GRP78在过表达TMEM16F组的表达量明显高于空载体组;TMEM16F sh RNA组与Scrambled组相比GRP78的表达量明显降低。2、在乳腺癌细胞MCf-7和T47D中,内质网应激的相关蛋白p-PERK/PERK,p-IRE1/IRE1表达量比值和蛋白ATf4表达在过表达TMEM16F组中明显高于空载体组,ATf6在两组间的表达无明显差异;TMEM16F sh RNA组与Scrambled组相比p-PERK/PERK,p-IRE1/IRE1的表达量比值与ATf4表达量降低,ATf6在两组间的表达无明显差异。3、TMEM16F可以促进MCf-7和T47D细胞的增殖,经PERK抑制剂处理过表达TMEM16F的MCf-7和T47D细胞后,细胞的增殖能力减弱。4、转染过表达TMEM16F载体的MCf-7和T47D细胞的迁移能力增强;转染TMEM16F sh RNA载体的MCf-7和T47D细胞较Scrambled sh RNA组的细胞迁移能力减弱。5、在过表达TMEM16F的MCf-7和T47D细胞中,经PERK抑制剂处理后的细胞的迁移能力减弱。6、在经BAPTA-AM和EGTA处理的乳腺癌MCf-7细胞中,TMEM16F对MCf-7细胞的促增殖作用被抑制。结论:1、TMEM16F促进乳腺癌细胞的内质网应激反应。2、TMEM16F促进内质网应激的PERK相关通路和IRE1蛋白表达,但不影响ATf6蛋白表达水平。3、TMEM16F促进乳腺癌细胞MCf-7和T47D的增殖和迁移。4、内质网应激中的PERK蛋白介导TMEM16F促进乳腺癌细胞MCf-7和T47D增殖和迁移。5、TMEM16F对乳腺癌细胞的促增殖作用依赖于Ca。

关键词： TMEM16F 乳腺癌内质网应激 PERK 增殖迁移

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TMEM16F调控P38/JNK信号通路介导阿尔茨海默病神经元凋亡的作用机制研究

TMEM16F调控P38/JNK信号通路介导阿尔茨海默病神经元凋亡的作用机...

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作者：何佳欢中国医科大学

学位级别：硕士

目的:本研究旨在探讨TMEM16F调控P38/JNK信号通路介导神经元凋亡在阿尔茨海默病(Alzheimer’s disease,AD)中的作用机制。研究方法:1、培养人神经母细胞瘤(SH-SY5Y)细胞,将细胞分为空白对照(Control)组、AD细胞模型(Model)组、si RNA阴... 详细信息

目的:本研究旨在探讨TMEM16F调控P38/JNK信号通路介导神经元凋亡在阿尔茨海默病(Alzheimer’s disease,AD)中的作用机制。研究方法:1、培养人神经母细胞瘤(SH-SY5Y)细胞,将细胞分为空白对照(Control)组、AD细胞模型(Model)组、si RNA阴性对照(si RNA-NC)组、si RNA-TMEM16F组。2、CCK-8法检测Aβ对SH-SY5Y细胞生存率的影响。3、将SH-SY5Y细胞用si RNA-NC、si RNA-TMEM16F进行转染,Aβ作用24h后收集。4、Western blotting检测沉默TMEM16F后各组细胞TMEM16F,AD病理指标Aβ、P-tau,凋亡相关因子Bcl-2、Bax、caspase-3及P38、JNK的蛋白表达水平。5、Real-Time PCR检测沉默TMEM16F后各组细胞TMEM16F,AD病理指标APP、tau,凋亡相关因子Bcl-2、Bax、caspase-3的m RNA表达水平。6、流式细胞仪检测沉默TMEM16F后细胞凋亡率的改变。7、TUNEL染色法检测沉默TMEM16F后细胞凋亡率的改变。8、JC-1法检测沉默TMEM16F后线粒体膜电位去极化的改变。9、MPTP法检测沉默TMEM16F后线粒体膜通透性转换孔开放的影响。结果:1、Aβ浓度≥20μmol/L,作用时间为24h时,细胞损伤明显,生存率显著下降(PTMEM16F的表达水平明显升高(PTMEM16F,APP、Aβ、tau、P-tau表达量显著降低(PTMEM16F,Bax、caspase-3表达量显著下降,Bcl-2表达量升高(PTMEM16F,细胞凋亡率显著下降(PTMEM16F,线粒体膜电位去极化水平下降(PTMEM16F,线粒体膜通透性转换孔开放程度下降(PTMEM16F,P38、JNK磷酸化水平显著下降(PTMEM16F在AD神经元中高表达,沉默TMEM16F对AD神经元具有保护作用。2、沉默TMEM16F使AD神经元凋亡减轻,且Aβ诱导的神经元凋亡的潜在机制可能由线粒体依赖途径介导。3、TMEM16F可能通过激活P38/JNK通路介导AD神经元凋亡。

关键词：阿尔茨海默病 TMEM16F 细胞凋亡 P38 JNK

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Plasma membrane lipid scrambling causing phosphatidylserine exposure negatively regulates NK cell activation

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Cellular & Molecular Immunology 2021年第3期18卷 686-697页

作者： Ning Wu Hua Song Andre Veillette Laboratory of Molecular Oncology Institut de recherches cliniques de Montreal(IRCM)MontrealQC H2W1R7Canada Department of Immunology School of Basic MedicineTongji Medical CollegeHuazhong University of Science and Technology(HUST)WuhanChina Department of Medicine University of MontrealMontrealQC H3C3J7Canada Department of Medicine McGill UniversityMontrealQC H3G 1Y6f Canada

One of the hallmarks of live cells is the asymmetric distribution of lipids across their plasma membrane.Changes in this asymmetry due to lipid"scrambling"result in phosphatidylserine exposure at the cell surface that is detected by annexin V staining.This alteration is observed during cell death processes such as apoptosis,and during physiological responses such as platelet degranulation and membrane repair.Previous studies have shown that activation of NK cells is accompanied by exposure of phosphatidylserine at the cell surface.While this response was thought to be indicative of ongoing NK cell death,it may also reflect the regulation of NK cell activation in the absence of cell death.Herein,we found that NK cell activation was accompanied by rapid phosphatidylserine exposure to an extent proportional to the degree of NK cell activation.Through enforced expression of a lipid scramblase,we provided evidence that activation-induced lipid scrambling in NK cells is reversible and does not lead to cell death.In contrast,lipid scrambling attenuates NKcell activation.This response was accompanied by reduced cell surface expression of activating receptors such as 2B4,and by loss of binding of Src family protein tyrosine kinases fyn and Lck to the inner leaflet of the plasma membrane.Hence,lipid scrambling during NK cell activation is,at least in part,a physiological response that reduces the NK cell activation level.This effect is due to the ability of lipid scrambling to alter the distribution of membrane-associated receptors and kinases required for NK cell activation.

关键词： NK cell activation Phosphatidylserine exposure Lipid scrambling TMEM16F Signaling

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