REGULATION OF HMGB1 BY KAPOSI`S SARCOMA ASSOSICATED HERPESVIRUS ENCODED LANA

Kaposi’s sarcoma associated herpesvirus (KSHV, HHV-8) is the etiological agent of Kaposi’s sarcoma (KS), and is tightly associated with primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD). KSHV is a member of the gamma-herpesvirus family and can establish life-long latent infection in human B lymphocytes and endothelial cells. The latency-associated nuclear antigen (LANA) is among the few KSHV encoded genes during latency. LANA is expressed in all forms of KSHV infected cells and promotes host-cell survival and viral genome maintenance. Previously, we have found an interaction between LANA and HMGB1, an important chromatin protein that also acts as cytokine mediator of Inflammation. Here we show that in KSHV-infected cells HMGB1 is re-localized into distinct foci within the nucleus. Co-localization studies reveal that HMGB1 co-localizes with LANA on the viral episomal genomes. Moreover, our data suggests that the B box element- the pro-inflammatory motif of HMGB1, is both essential and sufficient for re-distribution of the protein in KSHV infected cells. Furthermore, we found that the expression IL-1β -a known cytokine regulated by extracellular HMGB1 is disrupted in KSHV infected cells. These findings suggest that LANA can disrupt the proper localization and function of HMGB1 both as chromatin modulator and alarmin component, so KSHV-infected cells cannot alarm other cells about the infection. Such interference to HMGB1 proper functionality in KSHV infected cells might be another way of immune evasion by this oncogenic virus.