PDF(Pubmed)
Abstract：
The APOBEC3 family of DNA cytosine deaminases comprises an important arm of the innate antiviral defense system. The gamma-herpesviruses Epstein-Barr virus and Kaposi\'s sarcoma-associated herpesvirus and the alpha-herpesviruses herpes simplex virus (HSV)-1 and HSV-2 have evolved an efficient mechanism to avoid APOBEC3 restriction by directly binding to APOBEC3B and facilitating its exclusion from the nuclear compartment. The only viral protein required for APOBEC3B relocalization is the large subunit of the ribonucleotide reductase (RNR). Here, we ask whether this APOBEC3B relocalization mechanism is conserved with the beta-herpesvirus human cytomegalovirus (HCMV). Although HCMV infection causes APOBEC3B relocalization from the nucleus to the cytoplasm in multiple cell types, the viral RNR (UL45) is not required. APOBEC3B relocalization occurs rapidly following infection suggesting the involvement of an immediate early or early (IE/E) viral protein. In support of this possibility, genetic (IE1 mutant) and pharmacologic (cycloheximide) strategies that prevent the expression of IE/E viral proteins also block APOBEC3B relocalization. In comparison, the treatment of infected cells with phosphonoacetic acid, which interferes with viral late protein expression, still permits A3B relocalization. These results combine to indicate that the beta-herpesvirus HCMV uses an RNR-independent, yet phenotypically similar, molecular mechanism to antagonize APOBEC3B. IMPORTANCE Human cytomegalovirus (HCMV) infections can range from asymptomatic to severe, particularly in neonates and immunocompromised patients. HCMV has evolved strategies to overcome host-encoded antiviral defenses to achieve lytic viral DNA replication and dissemination and, under some conditions, latency and long-term persistence. Here, we show that HCMV infection causes the antiviral factor, APOBEC3B, to relocalize from the nuclear compartment to the cytoplasm. This overall strategy resembles that used by related herpesviruses. However, the HCMV relocalization mechanism utilizes a different viral factor(s) and available evidence suggests the involvement of at least one protein expressed at the early stages of infection. This knowledge is important because a greater understanding of this mechanism could lead to novel antiviral strategies that enable APOBEC3B to naturally restrict HCMV infection.
摘要：
DNA胞嘧啶脱氨酶的APOBEC3家族包括先天抗病毒防御系统的重要分支。γ-疱疹病毒爱泼斯坦-巴尔病毒和卡波西肉瘤相关疱疹病毒以及α-疱疹病毒单纯疱疹病毒（HSV）-1和HSV-2已经进化出一种有效的机制，可以通过直接结合APOBEC3B来避免APOBEC3限制并促进其从核室中排除。APOBEC3B重新定位所需的唯一病毒蛋白是核糖核苷酸还原酶（RNR）的大亚基。这里,我们询问这种APOBEC3B再定位机制是否与β-疱疹病毒人巨细胞病毒(HCMV)保守。尽管HCMV感染导致APOBEC3B在多种细胞类型中从细胞核重新定位到细胞质，病毒RNR（UL45）是不需要的。APOBEC3B重新定位在感染后迅速发生，提示立即早期或早期（IE/E）病毒蛋白的参与。为了支持这种可能性，阻止IE/E病毒蛋白表达的遗传(IE1突变体)和药理学(环己酰亚胺)策略也阻断APOBEC3B的再定位.相比之下,用膦酰基乙酸处理感染的细胞，干扰病毒晚期蛋白表达，仍然允许A3B重新定位。这些结果共同表明β-疱疹病毒HCMV使用非RNR，然而表型相似，拮抗APOBEC3B的分子机制。重要性人巨细胞病毒（HCMV）感染的范围从无症状到严重，尤其是新生儿和免疫功能低下的患者。HCMV已经进化的策略来克服宿主编码的抗病毒防御，以实现裂解病毒DNA复制和传播，在某些条件下,延迟和长期持久性。这里,我们表明，HCMV感染引起的抗病毒因子，APOBEC3B,从核室重新定位到细胞质。这种总体策略类似于相关疱疹病毒所使用的策略。然而,HCMV的再定位机制利用了不同的病毒因子，现有证据表明至少有一种在感染早期表达的蛋白质参与其中。这些知识很重要，因为对这种机制的更多理解可能导致新的抗病毒策略，使APOBEC3B能够自然地限制HCMV感染。
