Using luciferase reporter assays, LANA was found to downregulate the promoter activity of IL-22R1. When LANA was overexpressed in both 293T cells and HUVECs, IL-22R1 promoter activity was altered. Many evidences indicate that LANA is able to modulate transcription through two distinct mechanisms, interaction with upstream transcriptional regulators or direct binding of DNA. LANA has been shown to be able to down-regulate the expression of the virally-encoded K1 gene by directly binding to its promoter. However, there was no data to demonstrate whether LANA can also regulate cellular gene expression by binding to the cellular chromosome DNA. The DNA sequence required for LANA binding has been identified as the LBS. By DNA sequence analysis, an LBS-like sequence which differs only in one nucleotide with LBS reported by Garber et al., was identified in the 59 264 to 248 region upstream of the IL-22R1 gene. Our data further demonstrate that LANA can bind to this LBS-like sequence both in vitro and in vivo. Meanwhile, when the LBS-like region was mutated, the ability of LANA to downregulate IL-22R1 was dramatically reduced. We have shown that the C-terminus of LANA is responsible for LBS binding, and consistent with these observations, we observed that transiently transfected LANA-C alone can also reduce IL-22R1 promoter activity. The LBS-like sequence in the IL-22R1 promoter is located close to the transcription start site, and the binding of a large protein like LANA may compete with other transcription factors to cause transcriptional repression. This is the first report indicating that LANA can bind directly to the host genomic DNA to regulate cellular gene expression. A previous report has also shown that LANA can silence TbR II gene expression by associating with the promoter of TbR II and leading to its methylation and to the deacetylation of the proximal histone. Indeed, KSHV LANA can modulate host gene expression in a multiple ways. The IL-22R1 promoter lacks a TATA box near its transcription LY2109761 inquirer initiation site but contains a Sp1-like element. Thus, Sp1 probably plays a role in the regulation of IL-22R1 expression. Previous reports have indicated that LANA can upregulate survivin expression by forming a complex with Sp1 or Sp1-like proteins. When the LBS-like region was deleted from the IL-22R1 promoter, we did observe the full length of LANA still can down-regulate IL-22R1 expression at a lower level, but LANA-C can not. So we speculate that Sp1 may also be involved in the regulation of IL-22R1 expression by LANA. IL-22R1 belongs to the Class II cytokine receptors family. The expression levels of IL-22R1 and IL-20R2, which can form a receptor complex to be GDC-0879 side effects recoginzed by IL-20 and IL- 24, are found much lower in KS tissue than in normal tissue, suggesting that the function of the cytokines might be impaired in the KS lesion. IL- 20 is an anti-angiogenic cytokine, and IL- 24 has also been confirmed as a potent inhibitor of angiogenesis.