Kaposi's sarcoma herpesvirus latency-associated nuclear antigen broadly regulates viral gene expression and is essential for lytic infection.
Kaposi's sarcoma herpesvirus latency-associated nuclear antigen broadly regulates viral gene expression and is essential for lytic infection.
复制标题
DOI：
10.1371/journal.ppat.1011907
复制
发表时间：
2024-01
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
卡波西氏肉瘤疱疹病毒(KSHV)是导致艾滋病恶性的主要原因，目前的治疗方法有限。像所有疱疹病毒一样，KSHV感染可以是潜伏的，也可以是裂解的。KSHV潜伏相关核抗原(LANA)是病毒基因组在潜伏感染过程中持续存在的关键。LANA还通过拮抗KSHV裂解开关蛋白RTA的表达和功能来维持潜伏期。在这里，我们发现LANA空的KSHV不能裂解复制，这表明需要LANA。虽然LANA在部分允许裂解感染的细胞中促进了裂解基因和潜伏基因的表达，但在不允许的细胞中抑制了表达。重要的是，在非允许细胞中强制表达RTA导致了裂解性感染的诱导，LANA转向促进而不是抑制大多数裂解性病毒基因的表达。当基础病毒基因表达水平较高时，LANA促进表达，但在低基础水平时抑制表达，除非强行诱导RTA表达。LANA的作用是广泛的，但具有病毒基因特异性，可延伸到宿主EF1α启动子控制下的工程重组病毒GFP，但不能作用于宿主EF1α。综上所述，这些结果表明，除了在基因组维持中的重要作用外，LANA还广泛地调节病毒基因的表达，并且在裂解感染期间高水平的裂解基因表达是必需的。以LANA为目标的战略有望消除KSHV感染。卡波西氏肉瘤疱疹病毒(KSHV)是艾滋病患者癌症的主要原因，目前的治疗方法有限。像其他疱疹病毒一样，KSHV以两种形式感染细胞，导致潜伏感染或裂解感染。KSHV潜伏期相关核抗原(LANA)对病毒潜伏期至关重要，因为它在分裂细胞中维持着染色体外的病毒基因组。LANA还通过拮抗KSHV裂解开关蛋白RTA来维持潜伏期，RTA能够触发裂解复制。在这里，我们发现缺乏LANA的KSHV不能裂解感染，这表明LANA是裂解复制所必需的。此外，LANA可以对病毒基因表达产生双重影响。在部分允许裂解的KSHV感染的细胞中，LANA促进病毒基因的表达，但在不允许的细胞中抑制表达。在非允许细胞中强制表达RTA导致LANA切换为促进而不是抑制大多数裂解病毒基因的表达。我们发现，当病毒基因基础表达水平较高时，LANA促进表达，而LANA在较低基础水平抑制表达。这些结果表明，除了在基因组维持中的重要作用外，LANA在裂解感染期间发生的裂解基因表达水平的升高也是必需的。未来灭活LANA的方法有望消除KSHV感染。
Kaposi’s sarcoma herpesvirus (KSHV) is a leading cause of malignancy in AIDS and current therapies are limited. Like all herpesviruses, KSHV infection can be latent or lytic. KSHV latency-associated nuclear antigen (LANA) is essential for viral genome persistence during latent infection. LANA also maintains latency by antagonizing expression and function of the KSHV lytic switch protein, RTA. Here, we find LANA null KSHV is not capable of lytic replication, indicating a requirement for LANA. While LANA promoted both lytic and latent gene expression in cells partially permissive for lytic infection, it repressed expression in non-permissive cells. Importantly, forced RTA expression in non-permissive cells led to induction of lytic infection and LANA switched to promote, rather than repress, most lytic viral gene expression. When basal viral gene expression levels were high, LANA promoted expression, but repressed expression at low basal levels unless RTA expression was forcibly induced. LANA’s effects were broad, but virus gene specific, extending to an engineered, recombinant viral GFP under control of host EF1α promoter, but not to host EF1α. Together, these results demonstrate that, in addition to its essential role in genome maintenance, LANA broadly regulates viral gene expression, and is required for high levels of lytic gene expression during lytic infection. Strategies that target LANA are expected to abolish KSHV infection. Kaposi’s sarcoma herpesvirus (KSHV) is a leading cause of cancer in those with AIDS and current therapies are limited. Like other herpesviruses, KSHV infects cells in two forms, causing latent or lytic infection. KSHV latency-associated nuclear antigen (LANA) is essential for viral latency since it maintains the extrachromosomal viral genome in dividing cells. LANA also maintains latency by antagonizing the KSHV lytic switch protein, RTA, which is capable of triggering lytic replication. Here, we find KSHV lacking LANA is incapable of lytic infection, indicating LANA is required for lytic replication. Further, LANA can have dual effects on viral gene expression. In cells partially permissive for lytic KSHV infection, LANA promoted viral gene expression, but repressed expression in non-permissive cells. Forced RTA expression in non-permissive cells led to LANA switching to promote, rather than repress, most lytic viral gene expression. We found when basal viral gene expression levels were high, LANA promoted expression, while LANA repressed expression at low basal levels. These results show that, in addition to its essential role in genome maintenance, LANA is required for the elevated levels of lytic gene expression that occur during lytic infection. Future approaches that inactivate LANA are expected to abolish KSHV infection.
登录
查看更多内容
影响因子：
6.4
作者：
Wei S;Lu S;Liang L;Wang X;Li W;Li T;Chen L;Ju E;Zhang X;Lai Z;Huang Y;Lu X;Gao SJ
通讯作者：
Gao SJ
影响因子：
3.7
作者：
Cotter, MA;Robertson, ES
通讯作者：
Robertson, ES
RTA 和 LANA 竞争性调节 let-7a/RBPJ 信号来控制 KSHV 复制
影响因子：
5.2
作者：
Di C;Zheng G;Zhang Y;Tong E;Ren Y;Hong Y;Song Y;Chen R;Tan X;Yang L
通讯作者：
Yang L
影响因子：
4.8
作者：
An, FQ;Compitello, N;Renne, R
通讯作者：
Renne, R
影响因子：
5.4
作者：
Forrest, J. Craig;Paden, Clinton R.;Speck, Samuel H.
通讯作者：
Speck, Samuel H.