Understanding The Function Of Lmp1-ctar3 In Ebv-associated Lymphomas

Abstract

Epstein-Barr virus, a ubiquitous virus infecting most of the world’s population, utilizes the traditional B-cell maturation pathway of the adaptive immune system to establish a life-long infection in the host due to the ability of the virus to immortalize B-cells. Latent EBV infection is associated with distinct lymphoid malignancies, and latent membrane protein 1 (LMP1) has been identified as the primary oncoprotein associated with these lymphoid malignancies and the immortalization of naïve B-cells. The three C-terminal activating regions (CTARs) of LMP1 play a significant role in the transformation of a naïve B-cell by dysregulating the normal signaling pathways for cell maintenance and maturation thereby inducing the mature B-cell to continue proliferating without control, a classic hallmark of cancer. Our current research focuses on CTAR3, which resides between CTAR1 and CTAR2 and consists of an average of four and a half 11 amino acid repeats (11-aaR) and one-to-two proline-rich regions (PXXPXP). Previous research established an interaction between the CTAR3 and the JAK/STAT pathway via the proline-rich regions, but others have reported that CTAR3 was not necessary for the LMP1/JAK interaction or LMP1-mediated STAT activation. More recent work demonstrated a correlation between lower numbers of 11-aaR found in CTAR3 and increased pathogenesis; however, the exact role of the repetitive elements has not been elucidated. We hypothesized the repetitive elements found in LMP1 CTAR3 were necessary for the ability of CTAR3 to modulate the oncogenic nature of LMP1. Using GFP-tagged LMP1 expression constructs, we investigated the intracellular and extracellular trafficking of LMP1, cellular migration and protein solubility. While the number of 11-aaR found within LMP1 are variable in nature, we found that with the loss of the 11-aaR the normal biology of the oncoprotein was altered. We demonstrate that the repetitive elements of LMP1-CTAR3, specifically the 11-aaR, affect the biology of LMP1 including the stability and the intracellular and extracellular trafficking of LMP1, which can change the oncogenic potential of LMP1. We propose that targeting the functions of the CTAR3 repetitive elements may provide new advance therapeutic opportunities for patients with EBV-associated lymphomas.