Functional Comparison of Molluscum Contagiosum Virus vFLIP MC159 with Murine Cytomegalovirus M36/vICA and M45/vIRA Proteins
Functional Comparison of Molluscum Contagiosum Virus vFLIP MC159 with Murine Cytomegalovirus M36/vICA and M45/vIRA Proteins
复制标题
DOI：
10.1128/jvi.02729-15
复制
发表时间：
2016-03-01
影响因子：
5.4
通讯作者：
Brune, Wolfram
中科院分区：
文献类型：
--
作者：
Huettmann, Julia;Krause, Eva;Brune, Wolfram
传染性软疣病毒（MCV）基因MC 159编码病毒FLICE抑制蛋白（vFLIP），其抑制caspase-8介导的细胞凋亡。据报道，MC 159蛋白还通过与RIP 1和NEMO相互作用抑制程序性坏死（坏死性凋亡）并调节NF-κ B活化。MC 159在MCV感染期间的重要性仍然未知，因为没有用于该病毒的繁殖和遗传操作的系统。在这里，我们研究了MC 159在病毒感染过程中的功能，使用鼠巨细胞病毒（MCMV）作为替代病毒。将MC 159插入MCMV基因组中，取代M36或M45，这两个MCMV基因具有与报道的MC 159相似的功能。M36编码半胱天冬酶-8诱导的细胞凋亡的病毒抑制剂（vICA），M45编码RIP激活的病毒抑制剂（vIRA），其抑制RIP 1/RIP 3介导的坏死性凋亡。M45蛋白还通过与NEMO相互作用来阻断NF-κ B活化。当MCMV表达时，MC 159阻断肿瘤坏死因子α（TNF-α）诱导的感染细胞凋亡，并部分恢复MCMV在巨噬细胞中的复制。然而，MC 159不能完全取代M45，因为它不能抑制鼠细胞中的坏死性凋亡，但它能减少MCMV感染的人HT-29细胞中TNF-α诱导的坏死性凋亡。MC 159对NF-κ B的作用也不同于M45。MCMV编码的M45阻断了TNF-α和白细胞介素-1 β（IL-1 β）对NF-κ B的激活，而MC 159抑制了TNF-α诱导的NF-κ B激活，但不抑制IL-1 α诱导的NF-κ B激活。这些结果表明，MC 159的功能谱根据细胞类型和表达系统而不同，并且需要用于MCV增殖的细胞培养系统来确定假定的病毒基因功能的生物学相关性。
Molluscum contagiosum virus (MCV) gene MC159 encodes a viral FLICE inhibitory protein (vFLIP) that inhibits caspase-8-mediated apoptosis. The MC159 protein was also reported to inhibit programmed necrosis (necroptosis) and modulate NF-kappa B activation by interacting with RIP1 and NEMO. The importance of MC159 during MCV infection has remained unknown, as there is no system for propagation and genetic manipulation of this virus. Here we investigated the functions of MC159 during viral infection using murine cytomegalovirus (MCMV) as a surrogate virus. MC159 was inserted into the MCMV genome, replacing M36 or M45, two MCMV genes with functions similar to those reported for MC159. M36 encodes a viral inhibitor of caspase-8-induced apoptosis (vICA) and M45 a viral inhibitor of RIP activation (vIRA), which inhibits RIP1/RIP3-mediated necroptosis. The M45 protein also blocks NF-kappa B activation by interacting with NEMO. When expressed by MCMV, MC159 blocked tumor necrosis factor alpha (TNF-alpha)-induced apoptosis of infected cells and partially restored MCMV replication in macrophages. However, MC159 did not fully replace M45, as it did not inhibit necroptosis in murine cells, but it reduced TNF-alpha- induced necroptosis in MCMV-infected human HT-29 cells. MC159 also differed from M45 in its effect on NF-kappa B. While MCMV-encoded M45 blocked NF-kappa B activation by TNF-alpha and interleukin-1 beta (IL-1 beta), MC159 inhibited TNF-alpha -but not IL-1 alpha induced NF-kappa B activation in infected mouse fibroblasts. These results indicate that the spectrum of MC159' s functions differs depending on cell type and expression system and that a cell culture system for the propagation of MCV is needed to determine the biological relevance of presumed viral gene functions.