Latent membrane protein 1 of Epstein-Barr virus inhibits as well as stimulates gene expression

The latent membrane protein 1 (LMP-1) of Epstein-Barr virus (EBV) functiona lly resembles a constitutively active, CD40-like receptor and contributes t o the maintenance of proliferation of EBV-infected primary human B lymphocy tes. LMP-1 is targeted to the plasma membrane, where it binds TRAF, TRADD, and JAK molecules to activate NP-kappa B-, AP-1-, and STAT-dependent pathwa ys as does CD40. Yet LMP-1 appears to lack a ligand to regulate its signali ng. We have found that LMP-1, when expressed at physiologic levels, inhibit s gene expression detectably. Higher levels of LMP-1 expression eventually inhibit both the steady-state level of RNA produced from a BamHI C promoter reporter and general cellular protein synthesis. These findings indicate t hat LMP-1 can limit its signaling and that this control is manifest at two levels. The domain of LMP-1 that binds TRAF, TRADD, and JAK/STAT molecules is not required for this regulation. A derivative of LMP-1 that contains on ly its amino-terminal and membrane-spanning domains is sufficient to inhibi t reporter activity when the reporter genes are expressed from the BamHI C and LMP-1 promoters. This same derivative of LMP-1 in parallel assays is su fficient to inhibit wild-type LMP-1's stimulation of NF-kappa B-dependent g ene expression. We suggest that LMP-1 encodes stimulatory and inhibitory ac tivities; the latter could limit signaling in the apparent absence of ligan d-dependent down-regulation.