猪圆环病毒2型感染诱导PK-15细胞自噬机制研究
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摘要
猪圆环病毒2型(Porcine circovirus type2, PCV2)是圆环病毒科的成员,基因组为1768nt或1767nt,有3个ORFS。ORF1编码复制蛋白Rep, ORF2编码有免疫原性的衣壳蛋白Cap, ORF3编码蛋白可诱导凋亡。PCV2对猪的致病性主要表现为免疫系统损伤,可以引起淋巴结肿大、淋巴细胞减少等病变,使感染猪处于免疫抑制状态,与断奶仔猪多系统衰竭综合征(postweaning multisystemic wasting syndrome, PMWS)的发生密切相关,给养猪业造成巨大经济损失。
尽管PCV2感染后淋巴细胞减少甚至消失的机制尚有争论,但研究表明淋巴样组织被组织细胞取代可能与PCV2诱导凋亡有关。自噬在病毒感染过程中起重要的作用,一方面,自噬可通过降解病毒成分递呈抗原,激活先天免疫,从而达到清除病毒的目的；另一方面,病毒也演变机制逃逸自噬的清除,维持自身存活和复制。研究表明,自噬和凋亡过程可相互调节,凋亡可能和自噬共存在或两者之间存在着一种相互转换关系影响了病毒的感染过程。我们推测PCV2感染可能通过自噬途径导致细胞凋亡,从而引起组织病理学变化和免疫系统损伤。但有关PCV2诱导上述细胞反应及PCV2感染淋巴组织的病理学机制还有待深入研究。
本研究旨在探明(1)PCV2感染和细胞自噬之间的关系,影响自噬的关键病毒蛋白；(2)自噬对病毒复制的影响；(3)PCV2引起细胞自噬的信号传导途径及其关键信号分子。
1. PCV2感染PK-15细胞后,通过激光共聚焦、免疫印迹和电镜技术分析PCV2与自噬之间的关系。结果表明,与未感染细胞相比,PCV2感染可诱导细胞中eGFP-LC3点的聚集(代表自噬囊泡)(4.33vs27.51, P<0.01).提高了LC3-II/B-actin的比率(24h:1.00vs2.97, P<0.05;36h:1.29vs4.11, P<0.01),电镜结果也表明PCV2感染可诱导自噬泡的形成,说明PCV2感染可诱导PK-15细胞自噬。PCV2感染导致p62蛋白的降解,且在自噬溶酶体抑制剂氯喹存在的情况下,p62和LC3-Ⅱ蛋白水平显著高于(p62：0.83vs1.87,P<0.05；LC3-Ⅱ：2.02vs6.97,P<0.05)未处理组,说明PCV2感染加速了自噬底物的降解。LysoTracker或LAMP1和LC3共定位试验发现,PCV2感染促进了两者的共定位,说明PCV2感染诱导自噬溶酶体的形成,即诱导了完整自噬反应。利用病毒编码蛋白和截短表达载体转染PK-15细胞,激光共聚焦和免疫印迹结果表明,PCV2Cap蛋白能诱导自噬,并且其90-233位氨基酸是诱导自噬的关键区域。
2.用不同自噬阶段的抑制剂或诱导剂研究自噬过程对PCV2复制和Cap蛋白表达的影响。荧光定量和TCID50结果表明,不同自噬阶段的抑制剂抑制自噬后均显著降低了PCV2的复制(荧光定量：3-甲基腺嘌呤(3-MA):71.51vs8.96,P<0.01;氯喹(CQ):71.51vs2.74, P<0.001; siAtg5:14.78vs6.24, P<0..05; TCID50:3-MA:4.66vs3.69, P<0.01; CQ:4.66vs3.56, P<0.01; siAtg5:4.2vs3.3, P<0.05)和Cap蛋白的表达；相反,自噬的诱导增强了PCV2的复制(荧光定量：雷帕霉素(Rapamycin):3.52vs23.19, P<0.05;饥饿培养基(EBSS):3.52vs130.65, P<0.05; TCID50:Rapamycin:4.66vs5.09, P<0.05; EBSS:4.66vs5.13, P<0.05)和Cap蛋白的表达,说明自噬有利于PCV2复制。
3.许多信号通路能调节自噬过程。哺乳动物雷帕霉素靶蛋白(mTOR)是调节自噬最主要的蛋白,许多激酶,诸如：AMP激活蛋白激酶(AMPK)、胞外信号调节因子(ERK1/2)、肿瘤结节蛋白(TSC2)等是mTOR的上游调节因子。利用免疫印迹、免疫共沉淀和激光共聚焦技术分析PCV2感染诱导自噬形成的机制。结果表明,PCV2感染抑制mTOR并激活ERK1/2途径；UO126或siERK1/2处理PK-15细胞下调ERK1/2,可恢复mTOR的磷酸化水平,抑制自噬。此外,compound C (AMPK抑制剂)处理抑制了ERK1/2、TSC2的磷酸化水平和LC3-Ⅱ蛋白水平,但恢复了mTOR的磷酸化水平；UO126处理也抑制TSC2的磷酸化水平,但并没有抑制AMPK的磷酸化水平。siTSC2处理没有抑制AMPK和ERK1/2的磷酸化水平,但恢复了mTOR的磷酸化水平,抑制自噬。共免疫沉淀结果表明,ERK1/2-AMPK、ERK1/2-TSC2是互作的。以上研究结果表明,PCV2感染可通过AMPK/ERK/TSC2/mTOR信号途径激活自噬,为进一步研究PCV2的感染特性以及致病机制提供了重要的理论基础。
综上所述,本研究阐明了(1)PCV2感染诱导PK-15细胞自噬,且Cap蛋白的90-233位氨基酸是诱导自噬的关键区域；(2)自噬过程有利于PCV2复制；(3)PCV2可通过AMPK/ERK/TSC2/mTOR信号途径激活自噬。研究结果为深入研究PCV2的致病机制、探寻抗PCV2药物筛选的靶标奠定基础。
Porcine circovirus type2(PCV2), a member of the genus Circovirus of the Circoviridae family, is a small DNA virus with single-stranded circular genome (1767or1768bp in length). Three major open reading frames (ORFs) have been identified for PCV2, ORF1, named the rep gene, encodes a protein involved in virus replication, ORF2, named the cap gene, encodes a immunogenic capsid protein, and the third protein encoded by ORF3is associated with cell apoptosis. PCV2can affect the immune system of pig and induce the immune suppression. The affected pigs show lymphadenectasis and lymphocytopenia, which is closely associated with postweaning multisystemic wasting syndrome (PMWS). Now, PMWS incurs great economic loss to the pig industry and restricts seriously the development of pig industry.
Histopathologic lesion caused by PCV2infection is lymphoid follicles disappearance in lymphatic organization, however, recent study have showed that lymphoid tissue was replaced by histiocyte which may related to PCV2-induced apoptosis. On one hand, autophagy plays a key role in antiviral infections by degradation of viral components, presenting viral antigens, activating the immune response, on the other hand, the viruses can also escape the protective antiviral activity and maintain their own survival and replication by inducing autophagy of the host cells. A number of papers suggest that autophagy and apoptosis are co-adjust each other, and autophagy is prior to apoptosis. We speculate whether autophagy triggers apoptosis involved in PCV2infection. However, it remains largely unknown on the mechanisms of PCV2-induced lymphoid depletion in affected pigs.
This study was in an attempt to clarify (1) Interactions between PCV2infection and autophagy,(2) The effect of autophagy on the viral replication,(3) The signaling pathway and key signaling molecules involved in PCV2-induced autophagy.
1. We analyzed the relationship between PCV2infection and autophagy through the laser confocal microscope, immunoblotting and electron microscopy in PCV2-infected PK-15cells. Results showed that eGFP-LC3protein was able to aggregate to form puncta in autophagy-induced cells and it was found that more puncta appeared in PCV2-infected cells (4.33vs27.51, P<0.01) than in mock cells. The ratio of LC3-Ⅱ/β-actin evidently increased (24h:1.00vs2.97, P<0.05;36h:1.29vs4.11, P<0.01) in PCV2-infected cells compared to mock-treated cells. Transmission electron microscope showed that compared with mock cells, in which autophagic vacuoles were rarely seen, accrual of0.5-1.0μm double-membrane vacuoles in virus-infected cells were observed. PCV2infection caused p62protein degradation, and p62and LC3-Ⅱ protein level treated with autolysosome inhibitors chloroquine were significantly higher than that of untreated group (p62:0.83vs1.87, P<0.05; LC3-II:2.02vs6.97, P<0.05), suggesting PCV2infection accelerated the autophagy substrate degradation. Besides enhancement of colocalization of LysoTracker or LAMP1with LC3suggested induction of autolysosome formation after PCV2infection, suggesting the complete autophagy reaction. PK-15cells were transfected with vectors expressed Cap or the truncated Cap, results showed that the capsid protein could induce autophagosome formation, and amino acids90-233was the key area that induced autophagy.
2. We treated PK-15cells with different autophagy inhibitors or inducers, and analyzed them effect on progeny virus yield and capsid protein expression. The results from real-time PCR and TCID50showed that autophagy inhibitors significantly weakened the PCV2titer (real-time PCR:3-methyladenine (3-MA):71.51vs8.96, P<0.01; chloroquine (CQ):71.51vs2.74, P<0.001; TCID50:3-MA:4.66vs3.69, P<0.01; CQ:4.66vs3.56, P<0.01) and Cap protein expression. Autophagy induction increased PCV2titer (real-time PCR:Rapamycin:3.52vs23.19, P<0.05; Earle's balanced salts (EBSS):3.52vs130.65,P<0.05; TCID50:Rapa:4.66vs5.09, P<0.05; EBSS:4.66vs5.13, P<0.05) and Cap protein expression. These results indicate that autophagy could facilitate virus replication.
3. A number of signaling pathways have been reported in regulation of autophagy. The mammalian target of rapamycin (mTOR) pathway is a well-known pathways involved in the regulation of autophagy. AMPK (AMP-activated protein kinase), ERK1/2(the extracellular signal-regulated kinase1/2) and TSC2(tuberous sclerosis protein2) lie on the upstream of mTOR. We analyzed the mechanism PCV2-induced autophagy by Immunoblotting, co-immunoprecipitation and confocal microscopy. Results showed that PCV2infection inhibited mTOR and activated ERK1/2. UO126or siERK1/2down-regulated ERK1/2, recovered the phosphorylation levels of mTOR and inhibited autophagy. Besides, compound C (AMPK inhibitor) reduces ERK1/2and TSC2activity, but also recovers the expression of mTOR, thereby inhibiting autophagy in PCV2-infected PK-15cells. UO126down-regulated the phosphorylation levels of TSC2, but not inhibited AMPK activation. Knockdown of TSC2didn't inhibit AMPK and ERK1/2activation, but recovered the phosphorylation of mTOR and down-regulated LC3lipidation (LC3-Ⅱ). Co-immunoprecipitation results suggest that activated ERK1/2interacts with activated AMPK and TSC2. Taken together, these results suggest that PCV2might induce autophagy via AMPK/ERK/TSC2/mTOR signaling pathway in host cells, which may thus represent a pivotal mechanism for PCV2persistence and pathogenesis.
In conclusion, this study demonstrated that (1) PCV2infection induced autophagy in PK-15cells, and the viral capsid protein induces formation of autophagosomes, and amino acids90-233is a key site that induces autophagy,(2) Autophagy could facilitate virus replication,(3) PCV2might induce autophagy via AMPK/ERK/TSC2/mTOR signaling pathway in host cells. The achieved findings will help better understanding the pathogenesis of PCV2infections and provide clues to targets for screening novel antiviral chemicals.
尽管PCV2感染后淋巴细胞减少甚至消失的机制尚有争论,但研究表明淋巴样组织被组织细胞取代可能与PCV2诱导凋亡有关。自噬在病毒感染过程中起重要的作用,一方面,自噬可通过降解病毒成分递呈抗原,激活先天免疫,从而达到清除病毒的目的；另一方面,病毒也演变机制逃逸自噬的清除,维持自身存活和复制。研究表明,自噬和凋亡过程可相互调节,凋亡可能和自噬共存在或两者之间存在着一种相互转换关系影响了病毒的感染过程。我们推测PCV2感染可能通过自噬途径导致细胞凋亡,从而引起组织病理学变化和免疫系统损伤。但有关PCV2诱导上述细胞反应及PCV2感染淋巴组织的病理学机制还有待深入研究。
本研究旨在探明(1)PCV2感染和细胞自噬之间的关系,影响自噬的关键病毒蛋白；(2)自噬对病毒复制的影响；(3)PCV2引起细胞自噬的信号传导途径及其关键信号分子。
1. PCV2感染PK-15细胞后,通过激光共聚焦、免疫印迹和电镜技术分析PCV2与自噬之间的关系。结果表明,与未感染细胞相比,PCV2感染可诱导细胞中eGFP-LC3点的聚集(代表自噬囊泡)(4.33vs27.51, P<0.01).提高了LC3-II/B-actin的比率(24h:1.00vs2.97, P<0.05;36h:1.29vs4.11, P<0.01),电镜结果也表明PCV2感染可诱导自噬泡的形成,说明PCV2感染可诱导PK-15细胞自噬。PCV2感染导致p62蛋白的降解,且在自噬溶酶体抑制剂氯喹存在的情况下,p62和LC3-Ⅱ蛋白水平显著高于(p62：0.83vs1.87,P<0.05；LC3-Ⅱ：2.02vs6.97,P<0.05)未处理组,说明PCV2感染加速了自噬底物的降解。LysoTracker或LAMP1和LC3共定位试验发现,PCV2感染促进了两者的共定位,说明PCV2感染诱导自噬溶酶体的形成,即诱导了完整自噬反应。利用病毒编码蛋白和截短表达载体转染PK-15细胞,激光共聚焦和免疫印迹结果表明,PCV2Cap蛋白能诱导自噬,并且其90-233位氨基酸是诱导自噬的关键区域。
2.用不同自噬阶段的抑制剂或诱导剂研究自噬过程对PCV2复制和Cap蛋白表达的影响。荧光定量和TCID50结果表明,不同自噬阶段的抑制剂抑制自噬后均显著降低了PCV2的复制(荧光定量：3-甲基腺嘌呤(3-MA):71.51vs8.96,P<0.01;氯喹(CQ):71.51vs2.74, P<0.001; siAtg5:14.78vs6.24, P<0..05; TCID50:3-MA:4.66vs3.69, P<0.01; CQ:4.66vs3.56, P<0.01; siAtg5:4.2vs3.3, P<0.05)和Cap蛋白的表达；相反,自噬的诱导增强了PCV2的复制(荧光定量：雷帕霉素(Rapamycin):3.52vs23.19, P<0.05;饥饿培养基(EBSS):3.52vs130.65, P<0.05; TCID50:Rapamycin:4.66vs5.09, P<0.05; EBSS:4.66vs5.13, P<0.05)和Cap蛋白的表达,说明自噬有利于PCV2复制。
3.许多信号通路能调节自噬过程。哺乳动物雷帕霉素靶蛋白(mTOR)是调节自噬最主要的蛋白,许多激酶,诸如：AMP激活蛋白激酶(AMPK)、胞外信号调节因子(ERK1/2)、肿瘤结节蛋白(TSC2)等是mTOR的上游调节因子。利用免疫印迹、免疫共沉淀和激光共聚焦技术分析PCV2感染诱导自噬形成的机制。结果表明,PCV2感染抑制mTOR并激活ERK1/2途径；UO126或siERK1/2处理PK-15细胞下调ERK1/2,可恢复mTOR的磷酸化水平,抑制自噬。此外,compound C (AMPK抑制剂)处理抑制了ERK1/2、TSC2的磷酸化水平和LC3-Ⅱ蛋白水平,但恢复了mTOR的磷酸化水平；UO126处理也抑制TSC2的磷酸化水平,但并没有抑制AMPK的磷酸化水平。siTSC2处理没有抑制AMPK和ERK1/2的磷酸化水平,但恢复了mTOR的磷酸化水平,抑制自噬。共免疫沉淀结果表明,ERK1/2-AMPK、ERK1/2-TSC2是互作的。以上研究结果表明,PCV2感染可通过AMPK/ERK/TSC2/mTOR信号途径激活自噬,为进一步研究PCV2的感染特性以及致病机制提供了重要的理论基础。
综上所述,本研究阐明了(1)PCV2感染诱导PK-15细胞自噬,且Cap蛋白的90-233位氨基酸是诱导自噬的关键区域；(2)自噬过程有利于PCV2复制；(3)PCV2可通过AMPK/ERK/TSC2/mTOR信号途径激活自噬。研究结果为深入研究PCV2的致病机制、探寻抗PCV2药物筛选的靶标奠定基础。
Porcine circovirus type2(PCV2), a member of the genus Circovirus of the Circoviridae family, is a small DNA virus with single-stranded circular genome (1767or1768bp in length). Three major open reading frames (ORFs) have been identified for PCV2, ORF1, named the rep gene, encodes a protein involved in virus replication, ORF2, named the cap gene, encodes a immunogenic capsid protein, and the third protein encoded by ORF3is associated with cell apoptosis. PCV2can affect the immune system of pig and induce the immune suppression. The affected pigs show lymphadenectasis and lymphocytopenia, which is closely associated with postweaning multisystemic wasting syndrome (PMWS). Now, PMWS incurs great economic loss to the pig industry and restricts seriously the development of pig industry.
Histopathologic lesion caused by PCV2infection is lymphoid follicles disappearance in lymphatic organization, however, recent study have showed that lymphoid tissue was replaced by histiocyte which may related to PCV2-induced apoptosis. On one hand, autophagy plays a key role in antiviral infections by degradation of viral components, presenting viral antigens, activating the immune response, on the other hand, the viruses can also escape the protective antiviral activity and maintain their own survival and replication by inducing autophagy of the host cells. A number of papers suggest that autophagy and apoptosis are co-adjust each other, and autophagy is prior to apoptosis. We speculate whether autophagy triggers apoptosis involved in PCV2infection. However, it remains largely unknown on the mechanisms of PCV2-induced lymphoid depletion in affected pigs.
This study was in an attempt to clarify (1) Interactions between PCV2infection and autophagy,(2) The effect of autophagy on the viral replication,(3) The signaling pathway and key signaling molecules involved in PCV2-induced autophagy.
1. We analyzed the relationship between PCV2infection and autophagy through the laser confocal microscope, immunoblotting and electron microscopy in PCV2-infected PK-15cells. Results showed that eGFP-LC3protein was able to aggregate to form puncta in autophagy-induced cells and it was found that more puncta appeared in PCV2-infected cells (4.33vs27.51, P<0.01) than in mock cells. The ratio of LC3-Ⅱ/β-actin evidently increased (24h:1.00vs2.97, P<0.05;36h:1.29vs4.11, P<0.01) in PCV2-infected cells compared to mock-treated cells. Transmission electron microscope showed that compared with mock cells, in which autophagic vacuoles were rarely seen, accrual of0.5-1.0μm double-membrane vacuoles in virus-infected cells were observed. PCV2infection caused p62protein degradation, and p62and LC3-Ⅱ protein level treated with autolysosome inhibitors chloroquine were significantly higher than that of untreated group (p62:0.83vs1.87, P<0.05; LC3-II:2.02vs6.97, P<0.05), suggesting PCV2infection accelerated the autophagy substrate degradation. Besides enhancement of colocalization of LysoTracker or LAMP1with LC3suggested induction of autolysosome formation after PCV2infection, suggesting the complete autophagy reaction. PK-15cells were transfected with vectors expressed Cap or the truncated Cap, results showed that the capsid protein could induce autophagosome formation, and amino acids90-233was the key area that induced autophagy.
2. We treated PK-15cells with different autophagy inhibitors or inducers, and analyzed them effect on progeny virus yield and capsid protein expression. The results from real-time PCR and TCID50showed that autophagy inhibitors significantly weakened the PCV2titer (real-time PCR:3-methyladenine (3-MA):71.51vs8.96, P<0.01; chloroquine (CQ):71.51vs2.74, P<0.001; TCID50:3-MA:4.66vs3.69, P<0.01; CQ:4.66vs3.56, P<0.01) and Cap protein expression. Autophagy induction increased PCV2titer (real-time PCR:Rapamycin:3.52vs23.19, P<0.05; Earle's balanced salts (EBSS):3.52vs130.65,P<0.05; TCID50:Rapa:4.66vs5.09, P<0.05; EBSS:4.66vs5.13, P<0.05) and Cap protein expression. These results indicate that autophagy could facilitate virus replication.
3. A number of signaling pathways have been reported in regulation of autophagy. The mammalian target of rapamycin (mTOR) pathway is a well-known pathways involved in the regulation of autophagy. AMPK (AMP-activated protein kinase), ERK1/2(the extracellular signal-regulated kinase1/2) and TSC2(tuberous sclerosis protein2) lie on the upstream of mTOR. We analyzed the mechanism PCV2-induced autophagy by Immunoblotting, co-immunoprecipitation and confocal microscopy. Results showed that PCV2infection inhibited mTOR and activated ERK1/2. UO126or siERK1/2down-regulated ERK1/2, recovered the phosphorylation levels of mTOR and inhibited autophagy. Besides, compound C (AMPK inhibitor) reduces ERK1/2and TSC2activity, but also recovers the expression of mTOR, thereby inhibiting autophagy in PCV2-infected PK-15cells. UO126down-regulated the phosphorylation levels of TSC2, but not inhibited AMPK activation. Knockdown of TSC2didn't inhibit AMPK and ERK1/2activation, but recovered the phosphorylation of mTOR and down-regulated LC3lipidation (LC3-Ⅱ). Co-immunoprecipitation results suggest that activated ERK1/2interacts with activated AMPK and TSC2. Taken together, these results suggest that PCV2might induce autophagy via AMPK/ERK/TSC2/mTOR signaling pathway in host cells, which may thus represent a pivotal mechanism for PCV2persistence and pathogenesis.
In conclusion, this study demonstrated that (1) PCV2infection induced autophagy in PK-15cells, and the viral capsid protein induces formation of autophagosomes, and amino acids90-233is a key site that induces autophagy,(2) Autophagy could facilitate virus replication,(3) PCV2might induce autophagy via AMPK/ERK/TSC2/mTOR signaling pathway in host cells. The achieved findings will help better understanding the pathogenesis of PCV2infections and provide clues to targets for screening novel antiviral chemicals.
引文
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