目的锌指蛋白335(Zfp335)参与调控胸腺T细胞的早期发育和外周T细胞亚群的分化,本研究旨在探讨Zfp335调控调节性T细胞(Treg)在肿瘤免疫中的作用和机制。方法用他莫昔芬在Treg中特异性敲除Zfp335基因[Zfp335^(fl/fl)叉头盒P3(FOXP3)creERT...目的锌指蛋白335(Zfp335)参与调控胸腺T细胞的早期发育和外周T细胞亚群的分化,本研究旨在探讨Zfp335调控调节性T细胞(Treg)在肿瘤免疫中的作用和机制。方法用他莫昔芬在Treg中特异性敲除Zfp335基因[Zfp335^(fl/fl)叉头盒P3(FOXP3)creERT2],并构建MC38移植瘤模型。接种肿瘤后第7天,观察并测量肿瘤的大小,第12天剥离肿瘤组织,用流式细胞术检测野生型(WT)组和Zfp335敲除(Zfp335^(CKO))组小鼠肿瘤浸润淋巴细胞中CD4^(+)T细胞、CD8^(+)T细胞和Treg的比例,以及效应性Treg(eTreg)的线粒体功能。结果自接种肿瘤后第10天开始,Zfp335^(CKO)组肿瘤体积显著小于WT组。Zfp335^(CKO)组CD4^(+)T细胞和CD8^(+)T细胞的肿瘤浸润比例、及其对应的效应细胞比例显著高于WT组。Zfp335^(CKO)组CD4^(+)T细胞和CD8^(+)T细胞分泌细胞因子γ干扰素(IFN-γ)、肿瘤坏死因子α(TNF-α)的比例显著高于WT组,Zfp335^(CKO)组CD8^(+)T细胞分泌颗粒酶B(GzmB)的比例显著高于WT组。Zfp335^(CKO)组Treg、诱导性共刺激分子(ICOS)+Treg比例显著低于WT组。Zfp335^(CKO)组eTreg表达Mitotracker Deep Red的水平显著低于WT组。结论在肿瘤发生过程中,Treg特异性缺失Zfp335导致其活化减弱,与eTreg的线粒体功能降低有关;Zfp335^(CKO)小鼠肿瘤浸润的效应性T细胞增多、分泌杀伤性细胞因子增多,进而抵抗肿瘤发展。展开更多
Aluminum(Al)toxicity poses a significant constraint on field crop yields in acid soils.Zinc finger protein36(ZFP36)is well-documented for its pivotal role in enhancing tolerance to both drought and oxidative stress in...Aluminum(Al)toxicity poses a significant constraint on field crop yields in acid soils.Zinc finger protein36(ZFP36)is well-documented for its pivotal role in enhancing tolerance to both drought and oxidative stress in rice.This study unveils a novel function of ZFP36 modulated by abscisic acid(ABA)-dependent mechanisms,specifically aimed at alleviating Al toxicity in rice.Under Al stress,the expression of ZFP36significantly increased through an ABA-dependent pathway.Knocking down ZFP36 heightened Al sensitivity,while overexpressing ZFP36 conferred increased resistance to Al stress.Additionally,our investigations revealed a physical interaction between ZFP36 and pyruvate dehydrogenase kinase 1 in rice(OsPDK1).Biochemical assays further elucidated that OsPDK1 phosphorylates ZFP36 at the amino acid site 73–161.Subsequent experiments demonstrated that ZFP36 positively regulates the expression of ascorbate peroxidases(OsAPX1)and OsALS1 by binding to specific elements in their upstream segments in rice.Through genetic and phenotypic analyses,we unveiled that OsPDK1 influences ABA-triggered antioxidant defense to alleviate Al toxicity by interacting with ZFP36.In summary,our study underscores that pyruvate dehydrogenase kinase 1(OsPDK1)phosphorylates ZFP36 to modulate the activities of antioxidant enzymes via an ABA-dependent pathway,influencing tolerance of rice to soil Al toxicity.展开更多
文摘目的锌指蛋白335(Zfp335)参与调控胸腺T细胞的早期发育和外周T细胞亚群的分化,本研究旨在探讨Zfp335调控调节性T细胞(Treg)在肿瘤免疫中的作用和机制。方法用他莫昔芬在Treg中特异性敲除Zfp335基因[Zfp335^(fl/fl)叉头盒P3(FOXP3)creERT2],并构建MC38移植瘤模型。接种肿瘤后第7天,观察并测量肿瘤的大小,第12天剥离肿瘤组织,用流式细胞术检测野生型(WT)组和Zfp335敲除(Zfp335^(CKO))组小鼠肿瘤浸润淋巴细胞中CD4^(+)T细胞、CD8^(+)T细胞和Treg的比例,以及效应性Treg(eTreg)的线粒体功能。结果自接种肿瘤后第10天开始,Zfp335^(CKO)组肿瘤体积显著小于WT组。Zfp335^(CKO)组CD4^(+)T细胞和CD8^(+)T细胞的肿瘤浸润比例、及其对应的效应细胞比例显著高于WT组。Zfp335^(CKO)组CD4^(+)T细胞和CD8^(+)T细胞分泌细胞因子γ干扰素(IFN-γ)、肿瘤坏死因子α(TNF-α)的比例显著高于WT组,Zfp335^(CKO)组CD8^(+)T细胞分泌颗粒酶B(GzmB)的比例显著高于WT组。Zfp335^(CKO)组Treg、诱导性共刺激分子(ICOS)+Treg比例显著低于WT组。Zfp335^(CKO)组eTreg表达Mitotracker Deep Red的水平显著低于WT组。结论在肿瘤发生过程中,Treg特异性缺失Zfp335导致其活化减弱,与eTreg的线粒体功能降低有关;Zfp335^(CKO)小鼠肿瘤浸润的效应性T细胞增多、分泌杀伤性细胞因子增多,进而抵抗肿瘤发展。
基金provided by the National Natural Science Foundation of China (31901202,31672228)National Distinguished Expert Project (WQ20174400441)+2 种基金the Higher Education Department of Guangdong province (2020KCXTD025)Key Laboratory Project of Guangdong Province (2022B1212010015)the Australian Research Council (DP150101663)。
文摘Aluminum(Al)toxicity poses a significant constraint on field crop yields in acid soils.Zinc finger protein36(ZFP36)is well-documented for its pivotal role in enhancing tolerance to both drought and oxidative stress in rice.This study unveils a novel function of ZFP36 modulated by abscisic acid(ABA)-dependent mechanisms,specifically aimed at alleviating Al toxicity in rice.Under Al stress,the expression of ZFP36significantly increased through an ABA-dependent pathway.Knocking down ZFP36 heightened Al sensitivity,while overexpressing ZFP36 conferred increased resistance to Al stress.Additionally,our investigations revealed a physical interaction between ZFP36 and pyruvate dehydrogenase kinase 1 in rice(OsPDK1).Biochemical assays further elucidated that OsPDK1 phosphorylates ZFP36 at the amino acid site 73–161.Subsequent experiments demonstrated that ZFP36 positively regulates the expression of ascorbate peroxidases(OsAPX1)and OsALS1 by binding to specific elements in their upstream segments in rice.Through genetic and phenotypic analyses,we unveiled that OsPDK1 influences ABA-triggered antioxidant defense to alleviate Al toxicity by interacting with ZFP36.In summary,our study underscores that pyruvate dehydrogenase kinase 1(OsPDK1)phosphorylates ZFP36 to modulate the activities of antioxidant enzymes via an ABA-dependent pathway,influencing tolerance of rice to soil Al toxicity.
