Kaposi's sarcoma-associated herpesvirus-encoded LANA down-regulates IL-22R1 expression through a cis-acting element within the promoter region.
Kaposi's sarcoma-associated herpesvirus-encoded LANA down-regulates IL-22R1 expression through a cis-acting element within the promoter region.
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DOI：
10.1371/journal.pone.0019106
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发表时间：
2011-04-22
期刊：
影响因子：
3.7
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Su L;Liao Q;Wu Y;Chen X
卡波西肉瘤相关疱疹病毒（KSHV）被认为是卡波西肉瘤（KS）的必要但不充分的致病因子。所有形式的KS的特征在于梭形细胞的增殖，并且来自KS病变的大多数（>90%）梭形细胞潜伏地感染KSHV。在KSHV潜伏期，只有少数病毒基因表达。在这些潜伏基因中，ORF 73基因编码潜伏相关核抗原（拉娜），其对于KSHV潜伏感染的建立和维持至关重要。许多证据表明，许多细胞因子可以增加KS的发生率和侵袭性。在这项研究中，KS和正常组织的微阵列分析显示，多种细胞因子和细胞因子受体的调节KSHV潜伏感染。特别令人感兴趣的是，发现IL-22 R1转录水平在KS组织中下调。为了研究拉娜对IL-22 R1的可能调控，构建了IL-22 R1启动子，发现其含有LANA结合位点（LBS）。已证明拉娜通过直接结合位于IL-22 R1启动子区域内的LBS下调IL-22 R1表达。此外，KSHV潜伏感染的细胞表现出对IL-22刺激的反应受损。这些结果表明，拉娜可以调节宿主因子的表达，通过直接结合到因子的启动子内的顺式作用元件，以利于潜伏的病毒感染和抑制抗病毒免疫应答。
Kaposi's sarcoma-associated herpesvirus (KSHV) is considered to be a necessary, but not sufficient, causal agent of Kaposi's sarcoma (KS). All forms of KS are characterized by the proliferation of spindle-shaped cells, and most (>90%) spindle cells from KS lesions are latently infected with KSHV. During KSHV latency, only a few viral genes are expressed. Among those latent genes, the ORF 73 gene encodes the latency-associated nuclear antigen (LANA), which is critical for the establishment and maintenance of the latent KSHV infection. Much evidence suggests that many cytokines can increase the frequency and aggressiveness of KS. In this study, a microarray analysis of KS and normal tissues revealed that multiple cytokines and cytokine receptors are regulated by KSHV latent infection. Of special interest, IL-22R1 transcript level was found to be down-regulated in the KS tissue. To study the possible regulation of IL-22R1 by LANA, the IL-22R1 promoter was constructed and found to contain a LANA-binding site (LBS). LANA was demonstrated to down-regulate IL-22R1 expression via direct binding to the LBS located within the IL-22R1 promoter region. Furthermore, KSHV latently infected cells showed an impaired response to IL-22 stimulation. These results suggest that LANA can regulate host factor expression by directly binding to a cis-acting element within the factor's promoter to benefit latent viral infection and suppression of the antiviral immune response.
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