磷酸化HSP27对抗TNF-α诱导HeLa细胞凋亡的分子机制研究
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摘要
肿瘤坏死因子(TNF)-a是一多功能的细胞因子,调节包括细胞凋亡在内的许多细胞生物学进程。TNF-a通过与其受体结合发挥生物学作用,与TNF-a作用的受体有受体1(TNFR1)和受体2(TNFR2),TNFR1表达于几乎所有的组织细胞,是TNF-a的主要受体。在大多数细胞中,TNF-a通过与TNFR1结合,诱发促存活和促凋亡两条相反的信号途径。热休克蛋白27(HSP27)是一个重要的分子伴侣,属于低分子量热休克蛋白家族(分子量12-43KD),主要生物学作用包括：保护细胞免受多种刺激诱发的细胞凋亡；调节细胞骨架重塑；参与细胞增殖、分化的信号调节等。HSP27在多种不同刺激的作用下可以被磷酸化修饰,其主要的磷酸化修饰位点位于15,78和82位的丝氨酸上,一旦HSP27被磷酸化修饰,其分子结构从大分子多聚体解聚为小分子寡聚体、二聚体或单体,其生物学功能亦随之改变。许多研究表明HSP27的磷酸化水平与肿瘤细胞的转移能力和放化疗抵抗正相关,然而,也有研究表明磷酸化HSP27与肿瘤的进展呈负相关。因此,磷酸化HSP27在肿瘤中的作用仍然存在着争议。
在本研究中,我们观察了磷酸化HSP27在TNF-a诱导人宫颈癌细胞(HeLa)凋亡中的作用。通过研究我们发现：TNF-a刺激人宫颈癌HeLa细胞,HSP27被磷酸化,使用MK2特异性抑制剂CMPD1或下调MK2以及过表达HSP27磷酸突变体的方法证明：抑制HSP27磷酸化增强TNF-a诱导的HeLa细胞凋亡。而后,我们又分析了磷酸化HSP27对抗TNF-a诱导凋亡的分子机制。通过免疫共沉淀实验我们发现,TNF-a刺激HeLa细胞诱导HSP27与转化生长因子活化激酶1(TAK1)结合,有趣的是,CMPD1预处理HeLa细胞,抑制HSP27磷酸化,TNF-a诱导的两者间的结合量亦随之减弱,该结果意味着,在HSP27/TAK1复合物中包含磷酸化形式的HSP27。通过激光共聚焦实验检测两者间的共定位现象发现,未接受TNF-a刺激的HeLa细胞,HSP27和TAK1均匀分布于细胞胞质内,一旦接受TNF-a的刺激,两者均积聚在胞质的某一区域,并表现出明显的共定位现象。相反,抑制HSP27磷酸化,两者间的共定位现象明显减弱。采用MK2抑制剂或MK2干扰的方法,抑制HSP27磷酸化,及过表达HSP27磷酸化突变体HSP27-3D,我们进一步发现磷酸化HSP27可以调节TAK1的泛素化、磷酸化及下游信号促存活信号分子p38MAPK及ERK的活化。另外,我们的实验结果亦表明,抑制HSP27磷酸化促进了肿瘤坏死因子受体1相关死亡蛋白(TRADD)的泛素化,但是,HSP27磷酸化对TNF-a诱导的促凋亡复合体中TRADD-FADD复合物的形成并无明显影响作用。这些结果表明磷酸化HSP27对TAK1和TRADD的泛素化发挥相反的调节作用,而且,磷酸化HSP27主要通过影响TNF-a诱导的促存活信号发挥抗凋亡作用,对凋亡复合体中TRADD与FADD的结合并无明显影响。总之,我们的研究揭示,磷酸化HSP27通过与TAK1结合,调节其泛素化,磷酸化及下游分子p38MAPK和ERK的活化在TNF-a诱导的凋亡发挥抗凋亡作用。该研究表明,在HeLa细胞中磷酸化HSP27可以作为一个新的调节分子调控TNF-a诱导的细胞凋亡,为磷酸化HSP27在TNF-a诱导HeLa细胞凋亡中的保护作用提供了一个新的见解。
Tumour necrosis factor (TNF)-a is a multifunction cytokine that regulates critical cellular processes, including apoptosis. TNF-a itself exerts its biological effects interacting with two different receptors:TNFR1and TNFR2, TNFR1is the major receptor which expressed in almost all cell types, after binding to its TNFR1, TNF-a usually trigger both survival and apoptotic signals in various cell types. Heat shock protein27(HSP27), an important cellular chaperone, belongs to the small molecular weight heat shock protein (HSP) family (12-43kD), is believed to protect cells from apoptosis, regulate cytoskeletal remodeling, involve in regulating cell proliferation, differentiation signal. HSP27can be phosphorylation at serine residues15,78and82according to different stimuli. Once HSP27was phosphorylated it disaggregated from large oligomeric complexes to small oligomers, dimer or monomers, subsequently the biological functions of Hsp27were also changed. Many studies have shown that the phosphorylation status of HSP27correlates with the metastatic potential and chemotherapy and radiotherapy resistance of cancer cells. However, it has also been reported HSP27phosphorylation levels can also be inversely correlated with the progression of tumours. Thus, the role of HSP27phosphorylation in tumor is still contradiction.
In this study, we investigated the role of phosphorylated HSP27in TNF-α induced human cervical carcinoma (HeLa) cells apoptosis and found that HSP27was phosphorylated upon TNF-a stimulation and suppression of HSP27phosphorylation by specific inhibitor CMPD1or MAPKAPK2(MK2) knockdown and by overexpression of nonphosphorylated mutant and phospho-mimetic mutants demonstrated that attenuated HSP27phosphorylation enhanced the TNF-a-induced apoptosis. Then, we analyzed the molecular mechanism of HSP27phosphorylation in the antagonism of TNF-a induced apoptosis in HeLa cells. By coimmunoprecipitation, we observed that HSP27associated with transforming growth factor-β (TGF-β)-activated kinase1(TAK1) in response to TNF-a stimulation. and, interestingly, CMPD1pretreatment resulted in the reduced complex formation of HSP27and TAK1, suggesting that phosphorylated HSP27could be composed into the complex. The co-localization of HSP27and TAK1was also detected by confocal microscopy. Result showed that HSP27and TAK1distributed in cytoplasm in the untreated HeLa cells, while their immunostainings obviously superposed and congregated in a compartment of cytoplasm upon stimulation of TNF-a. By contrast, suppression of HSP27phosphorylation largely reduced the congregation of HSP27and TAK1. By using CMPD1to block MK2activity or direct knockdown of MK2in order to hinder HSP27phosphorylation and by overexpression phospho-mimetic mutants Hsp27-3D, we further founded that phosphorylation of HSP27regulated TAK1ubiquitination, phosphorylation, and activation of downstream pro-survival molecules p38MAPK and ERK. In addition, our data also showed inhibition HSP27phosphorylation can promote ubiquitination of TRADD, but did not affect the binding of TRADD and FADD in HeLa cells. These results suggested HSP27phosphorylation not only regulated the ubiquitination of TAK1but also TRADD ubiquitination, and, the effects of HSP27phosphorylation on the ubiquitianation of TAK1and TRADD was opposite. Moreover, HSP27phosphorylation only regulated the pro-survival signal pathway, but did not affect the association of TRADD and FADD in apoptotic complex induced by TNF-a in HeLa cells. Taken together, our study revealed that HSP27phosphorylation regulating TAK1ubiquitination, phosphorylation and activation of p38and ERK pro-survival signaling pathway via interacting with TAK1in HeLa cells. This study demonstrates that HSP27phosphorylation serves as a novel regulator in TNF-a-induced apoptosis, and provides a new insight into the cytoprotective role of HSP27phosphorylation.
在本研究中,我们观察了磷酸化HSP27在TNF-a诱导人宫颈癌细胞(HeLa)凋亡中的作用。通过研究我们发现：TNF-a刺激人宫颈癌HeLa细胞,HSP27被磷酸化,使用MK2特异性抑制剂CMPD1或下调MK2以及过表达HSP27磷酸突变体的方法证明：抑制HSP27磷酸化增强TNF-a诱导的HeLa细胞凋亡。而后,我们又分析了磷酸化HSP27对抗TNF-a诱导凋亡的分子机制。通过免疫共沉淀实验我们发现,TNF-a刺激HeLa细胞诱导HSP27与转化生长因子活化激酶1(TAK1)结合,有趣的是,CMPD1预处理HeLa细胞,抑制HSP27磷酸化,TNF-a诱导的两者间的结合量亦随之减弱,该结果意味着,在HSP27/TAK1复合物中包含磷酸化形式的HSP27。通过激光共聚焦实验检测两者间的共定位现象发现,未接受TNF-a刺激的HeLa细胞,HSP27和TAK1均匀分布于细胞胞质内,一旦接受TNF-a的刺激,两者均积聚在胞质的某一区域,并表现出明显的共定位现象。相反,抑制HSP27磷酸化,两者间的共定位现象明显减弱。采用MK2抑制剂或MK2干扰的方法,抑制HSP27磷酸化,及过表达HSP27磷酸化突变体HSP27-3D,我们进一步发现磷酸化HSP27可以调节TAK1的泛素化、磷酸化及下游信号促存活信号分子p38MAPK及ERK的活化。另外,我们的实验结果亦表明,抑制HSP27磷酸化促进了肿瘤坏死因子受体1相关死亡蛋白(TRADD)的泛素化,但是,HSP27磷酸化对TNF-a诱导的促凋亡复合体中TRADD-FADD复合物的形成并无明显影响作用。这些结果表明磷酸化HSP27对TAK1和TRADD的泛素化发挥相反的调节作用,而且,磷酸化HSP27主要通过影响TNF-a诱导的促存活信号发挥抗凋亡作用,对凋亡复合体中TRADD与FADD的结合并无明显影响。总之,我们的研究揭示,磷酸化HSP27通过与TAK1结合,调节其泛素化,磷酸化及下游分子p38MAPK和ERK的活化在TNF-a诱导的凋亡发挥抗凋亡作用。该研究表明,在HeLa细胞中磷酸化HSP27可以作为一个新的调节分子调控TNF-a诱导的细胞凋亡,为磷酸化HSP27在TNF-a诱导HeLa细胞凋亡中的保护作用提供了一个新的见解。
Tumour necrosis factor (TNF)-a is a multifunction cytokine that regulates critical cellular processes, including apoptosis. TNF-a itself exerts its biological effects interacting with two different receptors:TNFR1and TNFR2, TNFR1is the major receptor which expressed in almost all cell types, after binding to its TNFR1, TNF-a usually trigger both survival and apoptotic signals in various cell types. Heat shock protein27(HSP27), an important cellular chaperone, belongs to the small molecular weight heat shock protein (HSP) family (12-43kD), is believed to protect cells from apoptosis, regulate cytoskeletal remodeling, involve in regulating cell proliferation, differentiation signal. HSP27can be phosphorylation at serine residues15,78and82according to different stimuli. Once HSP27was phosphorylated it disaggregated from large oligomeric complexes to small oligomers, dimer or monomers, subsequently the biological functions of Hsp27were also changed. Many studies have shown that the phosphorylation status of HSP27correlates with the metastatic potential and chemotherapy and radiotherapy resistance of cancer cells. However, it has also been reported HSP27phosphorylation levels can also be inversely correlated with the progression of tumours. Thus, the role of HSP27phosphorylation in tumor is still contradiction.
In this study, we investigated the role of phosphorylated HSP27in TNF-α induced human cervical carcinoma (HeLa) cells apoptosis and found that HSP27was phosphorylated upon TNF-a stimulation and suppression of HSP27phosphorylation by specific inhibitor CMPD1or MAPKAPK2(MK2) knockdown and by overexpression of nonphosphorylated mutant and phospho-mimetic mutants demonstrated that attenuated HSP27phosphorylation enhanced the TNF-a-induced apoptosis. Then, we analyzed the molecular mechanism of HSP27phosphorylation in the antagonism of TNF-a induced apoptosis in HeLa cells. By coimmunoprecipitation, we observed that HSP27associated with transforming growth factor-β (TGF-β)-activated kinase1(TAK1) in response to TNF-a stimulation. and, interestingly, CMPD1pretreatment resulted in the reduced complex formation of HSP27and TAK1, suggesting that phosphorylated HSP27could be composed into the complex. The co-localization of HSP27and TAK1was also detected by confocal microscopy. Result showed that HSP27and TAK1distributed in cytoplasm in the untreated HeLa cells, while their immunostainings obviously superposed and congregated in a compartment of cytoplasm upon stimulation of TNF-a. By contrast, suppression of HSP27phosphorylation largely reduced the congregation of HSP27and TAK1. By using CMPD1to block MK2activity or direct knockdown of MK2in order to hinder HSP27phosphorylation and by overexpression phospho-mimetic mutants Hsp27-3D, we further founded that phosphorylation of HSP27regulated TAK1ubiquitination, phosphorylation, and activation of downstream pro-survival molecules p38MAPK and ERK. In addition, our data also showed inhibition HSP27phosphorylation can promote ubiquitination of TRADD, but did not affect the binding of TRADD and FADD in HeLa cells. These results suggested HSP27phosphorylation not only regulated the ubiquitination of TAK1but also TRADD ubiquitination, and, the effects of HSP27phosphorylation on the ubiquitianation of TAK1and TRADD was opposite. Moreover, HSP27phosphorylation only regulated the pro-survival signal pathway, but did not affect the association of TRADD and FADD in apoptotic complex induced by TNF-a in HeLa cells. Taken together, our study revealed that HSP27phosphorylation regulating TAK1ubiquitination, phosphorylation and activation of p38and ERK pro-survival signaling pathway via interacting with TAK1in HeLa cells. This study demonstrates that HSP27phosphorylation serves as a novel regulator in TNF-a-induced apoptosis, and provides a new insight into the cytoprotective role of HSP27phosphorylation.
引文
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