The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family

Abstract

The cytoplasmic C-terminus of Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1) is essential for B lymphocyte growth transformation and is now shown to interact with a novel human protein (LMP1-associated protein 1 [LAP1]). LAP1 is homologous to a murine protein, tumor necrosis factor receptor-associated factor 2 (TRAF2), implicated in growth signaling from the p80 TNFR. A second novel protein (EBI6), induced by EBV infection, is the human homolog of a second murine TNFR-associated protein (TRAF1). LMP1 expression causes LAP1 and EBI6 to localize to LMP1 clusters in lymphoblast plasma membranes, and LMP1 coimmunoprecipitates with these proteins. LAP1 binds to the p80 TNFR, CD40, and the lymphotoxin-beta receptor, while EBI6 associates with the p80 TNFR. The interaction of LMP1 with these TNFR family-associated proteins is further evidence for their role in signaling and links LMP1-mediated transformation to signal transduction from the TNFR family.

An Update on Epstein-Barr Virus and Nasopharyngeal Carcinogenesis

“…LMP1 is the main transforming protein of EBV and functions as a classic oncogene in fibroblast transformation assay [5]. LMP1 functions as an activated member of the tumor receptor (TNFR) superfamily, and activates several signaling pathways [6,7].…”

From receptors to stress-activated MAP kinases

“…The question marks indicate that direct evidence of these pathways remain to be established (TRAF2), which interacts directly with TNFR-2 (Rothe et al, 1994) but is recruited to TNFR-1 via its interaction with TNFR-1-associated death domain protein (TRADD; Hsu et al, 1995Hsu et al, , 1996b. To date, six members of the TRAF family have been identi®ed (Hu et al, 1994;Rothe et al, 1994;Cheng et al, 1995;Mosialos et al, 1995;Re gnier et al, 1995;Cao et al, 1996;Nakano et al, 1996). All TRAFs contain a conserved C-terminal TRAF domain that is used for homo-or hetero-oligomerization and for interaction with the cytoplasmic regions of the TNFR superfamily.…”

“…All TRAFs contain a conserved C-terminal TRAF domain that is used for homo-or hetero-oligomerization and for interaction with the cytoplasmic regions of the TNFR superfamily. With the exception of TRAF1, all TRAF proteins contain an N-terminal Ring ®nger and several zinc ®nger structures that are critical for their e ector functions (Hu et al, 1994;Rothe et al, 1994;Cheng et al, 1995;Mosialos et al, 1995;Re gnier et al, 1995;Cao et al, 1996;Nakano et al, 1996). Structural and biochemical analyses suggest that TRAFs do not possess enzymatic activity, in turn suggesting that they function as adaptor proteins.…”

Modulation of life and death by the TNF receptor superfamily

“…The Nterminal portion of the TRAF domain is somewhat less conserved, and appears to conform to the coiled-coil a helix motif (Rothe et al, 1994). While it is possible that the coiled-coil may account for the oligomeric qualities of TRAFs, additional experiments have implicated the more conserved C-terminal TRAF domain sequences in protein oligomerization in addition to their function in mediating TRAF protein-receptor interactions (Cheng et al, 1995;Hu et al, 1995;Mosialos et al, 1995;Rothe et al, 1995;Sato et al, 1995).…”