KAPOSI’S SARCOMA ASSOCIATED HERPESVIRUS ENCODED LANA PROTEIN RE-DISTRIBUTES HMGB1 INTO NUCLEAR FOCI TO PREVENT ITS SECRETION

High-mobility group box-1 protein (HMGB1) is a highly conserved nuclear DNA binding protein involved in DNA replication, transcription and DNA repair. In addition to its role in the nucleus, HMGB1 can be released passively during necrosis or actively during trauma and inflammation where it serves as “alarmin” molecule to alarm distant cells of invading pathogens. It can be released from immune and non-immune cells in response to various stimuli, contributing to numerous chronic inflammatory and autoimmune diseases. 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. During latent infection, only several viral genes are expressed, and these genes are known to promote host-cell survival and viral genome maintenance. The latency-associated nuclear antigen (LANA) is among these KSHV latency genes that consistently expressed in all forms of KSHV-positive tissues and cell lines. Previously, we have found an interaction between LANA and HMGB1. Here we show that in contrast to uninfected B-cells, KSHV infected B-cells do not secrete HMGB1 upon LPS treatment, a known inducer of HMGB1 secretion. Moreover, in KSHV-infected cells HMGB1 is re-localized into distinct foci within the nucleus. It seems that LANA induces this HMGB1 nuclear foci as this phenomenon is observed also in LANA-expressing cells. These findings suggest that LANA modulates the active secretion of HMGB1, so KSHV-infected cells cannot alarm other cells about the infection. Capturing of HMGB1 within infected cells might be another way of immune evasion by this oncogenic virus.