Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), a gamma-2 herpesvirus, is the causative agent of KS, primary effusion lymphoma (PEL), and a plasma cell variant of multicentric Castleman's disease. Although KSHV latency is detected in KS-related tumors, oncogenic pathways activated by KSHV latent infection are not fully understood. Here, we found that retrotransposition of long interspersed element-1 (L1), a retrotransposon in the human genome, was enhanced in PEL cells. Among the KSHV latent genes, viral FLICE-inhibitory protein (vFLIP) enhanced L1 retrotransposition in an NF-κB-dependent manner. Intracellular cell adhesion molecule-1 (ICAM-1), an NF-κB target, regulated the vFLIP-mediated enhancement of L1 retrotransposition. Furthermore, ICAM-1 downregulated the expression of Moloney leukemia virus 10 (MOV10), an L1 restriction factor. Knockdown of ICAM-1 or overexpression of MOV10 relieved the vFLIP-mediated enhancement of L1 retrotransposition. Collectively, during KSHV latency, vFLIP upregulates ICAM-1 in an NF-κB-dependent manner, which, in turn, downregulates MOV10 expression and thereby enhances L1 retrotransposition. Because active L1 retrotransposition can lead to genomic instability, which is commonly found in KS and PEL, activation of L1 retrotransposition during KSHV latency may accelerate oncogenic processes through enhancing genomic instability. Our results suggest that L1 retrotransposition may be a novel target for impeding tumor development in KSHV-infected patients.

中文翻译：

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卡波西氏肉瘤相关疱疹病毒的潜伏感染可增强长散布的element-1的逆转座。

卡波西氏肉瘤（KS）相关的疱疹病毒（KSHV），一种伽玛2疱疹病毒，是KS，原发渗出性淋巴瘤（PEL）和多中心Castleman病的浆细胞变异的病原体。尽管在KS相关肿瘤中检测到KSHV潜伏期，但尚未完全了解由KSHV潜伏感染激活的致癌途径。在这里，我们发现在人类PEL细胞中，长散布的element-1（L1）（人类基因组中的一个反转录转座子）的反转录增强了。在KSHV潜在基因中，病毒FLICE抑制蛋白（vFLIP）以NF-κB依赖性方式增强L1逆转座。细胞内细胞粘附分子-1（ICAM-1）是一种NF-κB靶标，它调节vFLIP介导的L1逆转座子的增强。此外，ICAM-1下调了莫洛尼白血病病毒10（MOV10）的表达，L1限制因素。抑制ICAM-1或MOV10的过表达缓解了vFLIP介导的L1逆转座子的增强。总的来说，在KSHV潜伏期中，vFLIP以NF-κB依赖性方式上调ICAM-1，进而下调MOV10表达，从而增强L1逆转座。由于活跃的L1逆转座会导致基因组不稳定，这在KS和PEL中很常见，因此在KSHV潜伏期中激活L1逆转座会通过增强基因组的不稳定性来加速致癌过程。我们的结果表明，L1逆转座可能是阻碍KSHV感染患者肿瘤发展的新靶标。vFLIP以NF-κB依赖性方式上调ICAM-1，进而下调MOV10表达，从而增强L1逆转座。由于活跃的L1逆转座会导致基因组不稳定，这在KS和PEL中很常见，因此在KSHV潜伏期中激活L1逆转座会通过增强基因组的不稳定性来加速致癌过程。我们的结果表明，L1逆转座可能是阻碍KSHV感染患者肿瘤发展的新靶标。vFLIP以NF-κB依赖性方式上调ICAM-1，进而下调MOV10表达，从而增强L1逆转座。由于活跃的L1逆转座会导致基因组不稳定，这在KS和PEL中很常见，因此在KSHV潜伏期中激活L1逆转座会通过增强基因组的不稳定性来加速致癌过程。我们的结果表明，L1逆转座可能是阻碍KSHV感染患者肿瘤发展的新靶标。KSHV潜伏期中L1逆转座的激活可能会通过增强基因组不稳定性来加速致癌过程。我们的结果表明，L1逆转座可能是阻碍KSHV感染患者肿瘤发展的新靶标。KSHV潜伏期中L1逆转座的激活可能会通过增强基因组不稳定性来加速致癌过程。我们的结果表明，L1逆转座可能是阻碍KSHV感染患者肿瘤发展的新靶标。