A Novel Inhibitor of the NF-κB Signaling Pathway Encoded by the Parapoxvirus Orf Virus
A Novel Inhibitor of the NF-κB Signaling Pathway Encoded by the Parapoxvirus Orf Virus
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DOI：
10.1128/jvi.02291-09
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发表时间：
2010-04-01
影响因子：
5.4
通讯作者：
Rock, D. L.
中科院分区：
文献类型：
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作者：
Diel, D. G.;Delhon, G.;Rock, D. L.
副痘病毒（parapoxvirus，ORFV）是绵羊和山羊的病原体，其已在若干动物物种中用作预防性和治疗性免疫调节剂。然而，由ORFV进化来调节和操纵免疫应答的功能（基因、蛋白质和作用机制）知之甚少。在此，新的ORFV蛋白ORFV 024显示抑制NF-κ B信号通路的活化，NF-κ B信号通路是针对病毒感染的早期免疫应答的重要调节剂。用ORFV 024缺失突变病毒感染原代绵羊细胞导致NF-κ B调节的趋化因子和其他促炎宿主基因的表达显著增加。ORFV 024在细胞培养物中的表达显著降低脂多糖（LPS）和肿瘤坏死因子α（TNF-α）诱导的NF-κ B应答报告基因表达。此外，ORFV 024表达降低了TNF-α诱导的NF-κ B-p65的磷酸化和核转位、I κ B α的磷酸化和降解以及I κ B激酶（IKK）亚基IKK α和IKK β的磷酸化，表明ORFV 024通过抑制IKK的活化而起作用，IKK是大多数NF-κ B活化刺激的瓶颈。尽管ORFV 024干扰NF-κ B信号通路的激活，但其从OV-IA 82基因组中的缺失对绵羊中的疾病严重程度、进展和消退时间没有显著影响，表明ORFV 024对于天然宿主中的病毒毒力不是必需的。这代表了由副痘病毒编码的NF-κ B抑制剂的首次描述。
The parapoxvirus orf virus (ORFV) is a pathogen of sheep and goats that has been used as a preventive and therapeutic immunomodulatory agent in several animal species. However, the functions (genes, proteins, and mechanisms of action) evolved by ORFV to modulate and manipulate immune responses are poorly understood. Here, the novel ORFV protein ORFV024 was shown to inhibit activation of the NF-kappa B signaling pathway, an important modulator of early immune responses against viral infections. Infection of primary ovine cells with an ORFV024 deletion mutant virus resulted in a marked increase in expression of NF-kappa B-regulated chemokines and other proinflammatory host genes. Expression of ORFV024 in cell cultures significantly decreased lipopolysaccharide (LPS)-and tumor necrosis factor alpha (TNF-alpha)-induced NF-kappa B-responsive reporter gene expression. Further, ORFV024 expression decreased TNF-alpha-induced phosphorylation and nuclear translocation of NF-kappa B-p65, phosphorylation, and degradation of I kappa B alpha, and phosphorylation of I kappa B kinase (IKK) subunits IKK alpha and IKK beta, indicating that ORFV024 functions by inhibiting activation of IKKs, the bottleneck for most NF-kappa B activating stimuli. Although ORFV024 interferes with activation of the NF-kappa B signaling pathway, its deletion from the OV-IA82 genome had no significant effect on disease severity, progression, and time to resolution in sheep, indicating that ORFV024 is not essential for virus virulence in the natural host. This represents the first description of a NF-kappa B inhibitor encoded by a parapoxvirus.