The NP9 protein encoded by the human endogenous retrovirus HERV‐K(HML‐2) negatively regulates gene activation of the Epstein‐Barr virus nuclear antigen 2 (EBNA2)

Abstract

Epstein-Barr virus (EBV) is a human tumour virus that efficiently growth-transforms primary human B-lymphocytes in vitro. The viral nuclear antigen 2 (EBNA2) is essential for immortalisation of B-cells and stimulates viral and cellular gene expression through interaction with DNA-bound transcription factors. Like its cellular homologue Notch, it associates with the DNA-bound repressor RBPJj (CSL/CBF1) thereby converting RBPJj into the active state. For instance, both EBNA2 and Notch activate the cellular HES1 promoter. In EBV-transformed lymphocytes, the RNA of the NP9 protein encoded by human endogenous retrovirus HERV-K(HML-2) Type 1 is strongly up-regulated. The NP9 protein is detectable both in EBV-positive Raji cells, a Burkitt's lymphoma cell line, and in IB4, an EBV-transformed human lymphoblastoid cell line. NP9 binds to LNX that forms a complex with the Notch regulator Numb. Therefore, the function of NP9 vis-à-vis Notch and EBNA2 was analysed. Here, we show that NP9 binds to EBNA2 and negatively affects the EBNA2-mediated activation of the viral C-and LMP2A promoters. In contrast, NP9 did neither interfere in the activation of the HES1 promoter by Notch nor the induction of the viral LMP1 promoter by EBNA2. In an electrophoretic mobility shift analysis, NP9 reduced the binding of EBNA2 to DNA-bound RBPJj by about 50%. The down-regulation of EBNA2-activity by NP9 might represent a cellular defence mechanism against viral infection or could, alternatively, represent an adaptation of the virus to prevent excessive viral protein production that might otherwise be harmful for the infected cell.

HIV-1 Infection Leads to Increased Transcription of Human Endogenous Retrovirus HERV-K (HML-2) ProvirusesIn Vivobut Not to Increased Virion Production

“…In addition, different HML-2 proviruses have different ORFs that dictate which retroviral proteins are expressed in vivo (7). Likewise, investigation into whether type 1 or type 2 proviruses are expressed differently during HIV-1 infection could elucidate new cellular functions for the accessory proteins Rec and Np9, as their expression is associated with malignancy (43,67,68).…”

Expression of Human Endogenous Retrovirus Type K (HML-2) Is Activated by the Tat Protein of HIV-1

“…1). Since Tat has been shown to activate both viral and cellular genes (15,52,86,90,110), and since we observed that Jurkat-Tat cells have higher HERV-K (HML-2) gag RNA expression compared to the parental Jurkat counterpart, we hypothesized that the HIV-1 Tat protein might play a role in activating HERV-K (HML-2) expression during HIV-1 infection.…”

“…The HERV-K (HML-2) proteins Rec and Np9 provide a potential link between HERV-K (HML-2) and oncogenesis (4,6,18,31,41,52,67,101). Both proteins have been shown to stimulate c-Myc expression by binding and inhibiting the c-myc gene repressor promyelocytic leukemia zinc-finger protein (PLZF [31]), and Rec has also recently been shown to interact with the testicular zinc-finger protein, another transcriptional repressor (67).…”

Potential Therapeutic Molecular Targets for Nasopharyngeal Carcinoma

“…Their mechanism of regulation is suggested by the binding of EBNA2 with cellular transcription factors RBPJ, CBF-2/AUF1 or Spi-1/PU.1 to specific response elements of each promoter (137). Recent work has demonstrated that human endogenous retrovirus K nuclear protein NP9 can bind to EBNA2 and negatively regulate the EBNA2-mediated activation of the EBV viral C-and LMP2A promoters (88). The carboxy-terminal acidic activation domain of EBNA2 is required for direct interaction with the CSL family of DNA-binding protein (CBF1) and participates in EBNA2-mediated gene transcription (306).…”