Abstract
Kaposi's sarcoma (KS) is caused by infection with Kaposi's sarcoma-associated herpesvirus (KSHV). The virus expresses unique microRNAs (miRNAs), but the targets and functions of these miRNAs are not completely understood. In order to identify human targets of viral miRNAs, we measured protein expression changes caused by multiple KSHV miRNAs using pulsed stable labeling with amino acids in cell culture (pSILAC) in primary endothelial cells. This led to the identification of multiple human genes that are repressed at the protein level, but not at the miRNA level. Further analysis also identified that KSHV miRNAs can modulate activity or expression of upstream regulatory factors, resulting in suppressed activation of a protein involved in leukocyte recruitment (ICAM1) following lysophosphatidic acid treatment, as well as up-regulation of a pro-angiogenic protein (HIF1α), and up-regulation of a protein involved in stimulating angiogenesis (HMOX1). This study aids in our understanding of miRNA mechanisms of repression and miRNA contributions to viral pathogenesis.
Highlights
At our current understanding, the herpesvirus family is the only viral family expressing multiple miRNAs
In addition to identifying previous microRNA targets and discovering new microRNA targets, we found the function of specific viral microRNAs to be associated with immune evasion and the expansion of blood vessel networks, a hallmark of Kaposi’s sarcoma
In order to identify the target genes repressed by Kaposi’s sarcoma-associated herpesvirus (KSHV) miRNAs, we measured the effects of KSHV miRNAs on protein expression by introducing viral miRNAs into uninfected primary endothelial cells (HUVEC)
Summary
The herpesvirus family is the only viral family expressing multiple miRNAs. Identified human targets include thrombospondin [4], BACH-1 [5,6], BCL-2 associated factor [7], MICB [8], musculoaponeurotic fibrosarcoma oncogene homolog [9], IkBa [10], Rbl2 [11], p21 [12], caspase 3 [13], TWEAKR [14], TGFbR2 [15], and other targets. These targets represent host genes involved in angiogenesis, transcription regulation, immune evasion, NF-kB regulation, epigenetic modifications, apoptosis and cell cycle regulation
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