Rotavirus Nonstructural Protein 1 Suppresses Virus-Induced Cellular Apoptosis To Facilitate Viral Growth by Activating the Cell Survival Pathways during Early Stages of Infection
Rotavirus Nonstructural Protein 1 Suppresses Virus-Induced Cellular Apoptosis To Facilitate Viral Growth by Activating the Cell Survival Pathways during Early Stages of Infection
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DOI：
10.1128/jvi.00225-10
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发表时间：
2010-07-01
影响因子：
5.4
通讯作者：
Chawla-Sarkar, Mamta
中科院分区：
文献类型：
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作者：
Bagchi, Parikshit;Dutta, Dipanjan;Chawla-Sarkar, Mamta
在病毒感染后，限制病毒传播的细胞反应之一是诱导细胞凋亡。在本研究中，我们报告的作用轮状病毒非结构蛋白1（NSP 1）通过激活促生存途径，如磷脂酰肌醇3-激酶（PI3 K）/Akt和NF-κ B（核因子κ B）在感染的早期（2至8 hpi）调节细胞凋亡。在MA 104或HT 29细胞中，与同基因野生型菌株A5 - 13相比，NSP 1突变菌株A5 - 16诱导Akt（蛋白激酶B）和p65 NF-κ B的微弱和瞬时激活。A5 - 16株感染后NF-κ B启动子活性或Akt磷酸化较弱，而转染NSP1质粒的细胞在感染轮状病毒A5 - 16株后，NF-κ B启动子活性或Akt磷酸化较弱。在感染A5 - 13或转染pcD-NSP1的细胞中，观察到NSP1与磷酸肌醇3-激酶（PI3K）的免疫共沉淀，表明PI3K/Akt的强烈激活可能是由于其与NSP1的相互作用。此外，在以相同的感染复数感染后，在复制周期结束时，与A5 - 13毒株相比，A5 - 16显示出减少的病毒颗粒数量。较低的生长速率可能是由于PI3 K/Akt和NF-κ B的弱诱导，因为A5 - 13菌株在PI3 K或NF-κ B抑制剂存在下也显示生长降低。这种影响是干扰素独立的，但是，它部分是由于显着更高的caspase-3活性，聚ADP核糖聚合酶（PARP）裂解，和细胞凋亡感染的早期阶段与NSP1突变体。因此，我们的数据表明，NSP1积极支持轮状病毒的生长，通过抑制过早凋亡改善病毒感染后的生长。
Following virus infection, one of the cellular responses to limit the virus spread is induction of apoptosis. In the present study, we report role of rotavirus nonstructural protein 1 (NSP1) in regulating apoptosis by activating prosurvival pathways such as phosphatidylinositol 3-kinase (PI3K)/Akt and NF-kappa B (nuclear factor kappa B) during early hours of infections (2 to 8 hpi). The NSP1 mutant strain A5-16 induces weak and transient activation of Akt (protein kinase B) and p65 NF-kappa B compared to the isogenic wild-type strain A5-13 in MA104 or HT29 cells. The weak NF-kappa B promoter activity or Akt phosphorylation after A5-16 infection could be complemented in cells transfected with plasmid expressing NSP1 after infection with the rotavirus A5-16 strain. In cells either infected with A5-13 or transfected with pcD-NSP1, coimmunoprecipitation of NSP1 with phosphoinositide 3-kinase (PI3K) was observed, indicating that strong activation of PI3K/Akt could be due to its interaction with NSP1. In addition, after infection with same multiplicity of infection, A5-16 showed reduced number of viral particles compared to the A5-13 strain at the end of the replication cycle. A lower growth rate could be due to weak induction of PI3K/Akt and NF-kappa B, since the A5-13 strain also showed reduced growth in the presence of PI3K or NF-kappa B inhibitors. This effect was interferon independent; however, it was partly due to significantly higher caspase-3 activity, poly-ADP ribose polymerase (PARP) cleavage, and apoptosis during earlier stages of infection with the NSP1 mutant. Thus, our data suggest that NSP1 positively supports rotavirus growth by suppression of premature apoptosis for improved virus growth after infection.