Latent membrane protein 1of Epstein-Barr virus mimics a constitutively active receptor molecule

Abstract

Latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is an integral membrane protein whichhas transforming potential and is necessary but not sufficient for B-cell immortalization by EBV. LMP1 molecules aggregate in the plasma membrane and recruit tumour necrosis factor receptor (TNF-R) -associated factors (TRAFs) which are presumably involved in the signalling cascade leading to NF-κB activation by LMP1. Comparable activities are mediated by CD40 and other members of the TNF-R family, which implies that LMP1 could function as a receptor. LMP1 lacks extended extracellular domains similar to β-adrenergic receptors but, in contrast, it also lacks any motifs involved in ligand binding. By using LMP1 mutants which can be oligomerized at will, we show that the function of LMP1 in 293 cells and B cells is solely dependent on oligomerization of its carboxyterminus. Biochemically, oligomerization is an intrinsic property of the transmembrane domain of wild-type LMP1 and causes a constitutive phenotype which can be conferred to the signalling domains of CD40 or the TNF-2 receptor. In EBV, immortalized B cells crosslinking in conjunction with membrane targeting of the carboxy-terminal signalling domain of LMP1 is sufficient for its biological activities. Thus, LMP1 acts like a constitutively activated receptor whose biological activities are ligand-independent.

Targeting NF-κB in hematologic malignancies

“…15 In particular, LMP1 can mimic CD40 signaling, and this could explain how latent EBV infection causes the upregulation of antiapoptotic target genes via NF-kB. 16 In EBV-negative HL, other mechanisms have been suggested to explain constitutive NF-kB activity in HRS cells. Thus, inactivating mutations in the IkB gene were found in several studies of EBV-negative HLs.…”

Epstein-Barr virus transformation: involvement of latent membrane protein 1-mediated activation of NF-κB

“…The cytoplasmic N-terminal domain tethers the ®rst membrane-spanning domain to the cytoplasm, but no sequences within this domain are essential for EBV growth transformation (Izumi et al, 1994). The six transmembrane domains cause LMP1 to spontaneously aggregate within the plasma membrane which enables two sites in the C-terminal cytoplasmic domain (CTD) to interact with cellular proteins and mediate signaling (Floettmann and Rowe, 1997;Gires et al, 1997;Hatzivassiliou et al, 1998;Liebowitz et al, 1986). Recombinant viral genetic and biochemical analyses show that these two sites in the CTD of LMP1 are critical for growth transformation and activation of NF-kB (Huen et al, 1995;Kaye et al, 1995;Mitchell and Sugden, 1995).…”

The Viral Etiology of AIDS‐Associated Malignancies

“…LMP-1 is an integral membrane protein with six transmembrane-spanning domains and a long C-terminal domain located in the cytoplasm Liebowitz et al, 1986). LMP-1 acts as a constitutively active, receptor-like molecule that does not need the binding of a ligand (Gires et al, 1997). The six transmembrane domains mediate oligomerization of LMP-1 molecules in the plasma membrane, a prerequisite for LMP-1 function (Floettmann and Rowe, 1997;Gires et al, 1997).…”

“…LMP-1 acts as a constitutively active, receptor-like molecule that does not need the binding of a ligand (Gires et al, 1997). The six transmembrane domains mediate oligomerization of LMP-1 molecules in the plasma membrane, a prerequisite for LMP-1 function (Floettmann and Rowe, 1997;Gires et al, 1997). Two regions in the C-terminus of LMP-1 have been shown to initiate signaling processes, the C-terminal activator regions 1 (CTAR-1, amino acids 194-231) and 2 (CTAR-2, amino acids 332-386) (Huen et al, 1995;Mitchell and Sugden, 1995).…”