EBV LMP-2A employs a novel mechanism to transactivate the HERV-K18 superantigen through its ITAM

Abstract

EBV encodes latent membrane protein (LMP)-2A that functions as a homologue of the activated BCR. We have previously shown that LMP-2A transactivates a human endogenous retrovirus, HERV-K18, in infected B-lymphocytes. The Env protein of HERV-K18 encodes a superantigen that strongly stimulates a large number of T cells. To delineate the mechanism through which LMP-2A transactivates HERV-K18 env, we tested a panel of tyrosine mutants of LMP-2A in a murine B lymphoma that stably harbors HERV-K18. Our analysis revealed that the immunoreceptor tyrosine-based activation motif (ITAM) of LMP-2A is important for HERV-K18 env transactivation. ITAM contains 2 tyrosines that initiate signaling cascades when both residues are phosphorylated. However, in our study, single-tyrosine mutants of ITAM still retained full induction of HERV-K18 env. After truncating 25 kb of genomic sequence downstream of HERV-K18, LMP-2A failed to transactivate HERV-K18 env. Thus, an LMP-2A-inducible element is located downstream of HERV-K18.

Expression of Dual-Specificity Phosphatase 5 Pseudogene 1 (DUSP5P1) in Tumor Cells

“…In addition to the mentioned viruses, retroviruses have been implicated in HL pathogenesis [37]. Interestingly, links between putative HL-associated viruses (EBV, HHV6, TTV) and endogenous retroviruses have been established [38]–[42]. EBV and HHV6 can induce expression of endogenous retroviruses [37], [38].…”

“…Interestingly, links between putative HL-associated viruses (EBV, HHV6, TTV) and endogenous retroviruses have been established [38]–[42]. EBV and HHV6 can induce expression of endogenous retroviruses [37], [38]. High prevalence of these viruses or immunoreactivity against viral antigens in patients with autoimmune diseases including multiple sclerosis (MS) has been observed [40]–[42].…”

B cells and monocytes from patients with active multiple sclerosis exhibit increased surface expression of both HERV-H Env and HERV-W Env, accompanied by increased seroreactivity

“…It is already established that herpesviruses can activate HERVs [7-9,37-40] and it is likely that reactivated herpesviruses may transactivate HERVs at the transcriptional level. Many indications also exist that herpesviruses may be involved in MS pathogenesis.…”

Expression of human endogenous retrovirus HERV-K18 is associated with clinical severity in osteoarthritis patients

“…In recent years it has been reported that common infections of different herpesviruses such as human herpesvirus 6A (29), human herpesvirus 6B (25), and Epstein-Barr virus (EBV) (20,21,30) are able to transactivate the HERV-K18 encoded superantigen. Furthermore, in a previous study of our group (31), we described the presence of EBV in two out of 12 samples of human cartilage obtained from patients with OA, but not in controls, suggesting the risk of EBV transmission or reactivation in a subset of patients with disorders requiring tissue regeneration.…”