Regulation of ICP0-Null Mutant Herpes Simplex Virus Type 1 Infection by ND10 Components ATRX and hDaxx
Regulation of ICP0-Null Mutant Herpes Simplex Virus Type 1 Infection by ND10 Components ATRX and hDaxx
复制标题
DOI：
10.1128/jvi.02597-09
复制
发表时间：
2010-04-01
影响因子：
5.4
通讯作者：
Everett, Roger D.
中科院分区：
文献类型：
--
作者：
Lukashchuk, Vera;Everett, Roger D.
单纯疱疹病毒 1 型 (HSV-1) 立即早期基因产物 ICP0 激活裂解性感染并缓解细胞介导的病毒基因表达抑制。这种抑制是由预先存在的细胞蛋白赋予的，通常被称为内在抗病毒耐药性或内在防御。 PML 和 Sp100 是被称为 ND10 或 PML 核体的核亚结构的两个核心成分，有助于内在抵抗，但很明显，其他蛋白质也必须参与其中。我们已经检验了这样的假设：额外的 ND10 因子，特别是那些参与染色质重塑的因子，可能在抵抗 HSV-1 感染的内在抵抗力中发挥作用。本报告中研究的两种 ND10 成分蛋白是 ATRX 和 hDaxx，已知它们会相互作用，并构成抑制性染色质重塑复合物的成分。我们生成了稳定的细胞系，其中内源性 ATRX 或 hDaxx 表达受到 RNA 干扰的严重抑制。我们发现在 ATRX 和 hDaxx 耗尽的细胞中，ICP0 缺失突变体 HSV-1 诱导基因表达和噬斑形成增加。野生型 hDaxx 表达的重建逆转了 hDaxx 缺失的影响，但用无法与 ATRX 相互作用的 hDaxx 突变形式重建却没有。我们的结果表明，ATRX 和 hDaxx 作为一种复合物，有助于对 HSV-1 感染产生内在的抗病毒耐药性，而 ICP0 可以抵消这种耐药性。
Herpes simplex virus type 1 (HSV-1) immediate-early gene product ICP0 activates lytic infection and relieves cell-mediated repression of viral gene expression. This repression is conferred by preexisting cellular proteins and is commonly referred to as intrinsic antiviral resistance or intrinsic defense. PML and Sp100, two core components of nuclear substructures known as ND10 or PML nuclear bodies, contribute to intrinsic resistance, but it is clear that other proteins must also be involved. We have tested the hypothesis that additional ND10 factors, particularly those that are involved in chromatin remodeling, may have roles in intrinsic resistance against HSV-1 infection. The two ND10 component proteins investigated in this report are ATRX and hDaxx, which are known to interact with each other and comprise components of a repressive chromatin-remodeling complex. We generated stable cell lines in which endogenous ATRX or hDaxx expression is severely suppressed by RNA interference. We found increases in both gene expression and plaque formation induced by ICP0-null mutant HSV-1 in both ATRX-and hDaxx-depleted cells. Reconstitution of wild-type hDaxx expression reversed the effects of hDaxx depletion, but reconstitution with a mutant form of hDaxx unable to interact with ATRX did not. Our results suggest that ATRX and hDaxx act as a complex that contributes to intrinsic antiviral resistance to HSV-1 infection, which is counteracted by ICP0.