Effects of the NIK aly Mutation on NF-κB Activation by the Epstein-Barr Virus Latent Infection Membrane Protein, Lymphotoxin β Receptor, and CD40

Epstein–Barr virus-encoded latent infection membrane protein 1 regulates the processing of p100 NF-κB2 to p52 via an IKKγ/NEMO-independent signalling pathway

“…However, LMP1 does not bind the IKK complex directly and mediates NF-kB signalling via adapter proteins of the TRAF family capable of recruiting NIK and IKKs (Sylla et al, 1998). We have found that overexpression of a NIK mutant that contains only the TRAF-interacting domain of NIK and is known to suppress LMP1-mediated NF-kB transcriptional activity (Luftig et al, 2001), abolished the effects of LMP1 on p100 processing (Figure 7). Therefore, the recruitment of an NIK-dependent but IKKg-independent signalling complex to LMP1 mediates the activation of the atypical p100 NF-kB2 pathway.…”

“…Unlike WT NIK, the aly mutant or a mutated NIK carrying only the TRAF-interacting domain ) fail to process p100 and have deleterious consequences for the ability of BAFF, CD40L or LTb to stimulate the generation of p52 (Xiao et al, 2001b;Claudio et al, 2002;Coope et al, 2002;Dejardin et al, 2002). These effects have been attributed to the inability of aly NIK to interact with IKKa (Luftig et al, 2001). Indeed, in cells lacking this IKK subunit, p100 processing in response to BAFF or LTb stimulation is impaired.…”

“…RSV-p100 NF-kB2 was a generous gift from Dr Neil Perkins, University of Dundee, UK. NIKD contains aa 624-947 of human NIK and was PCR amplified from a WT NIK-containing plasmid (kindly provided by Dr D Wallach, Rehovot, Israel; Malinin et al, 1997), as previously described (Luftig et al, 2001). It was then cloned as a BamHI/EcoRI fragment in frame into pRK5myc (Lamarche et al, 1996).…”

“…A mutated NIK molecule, expressing only its TRAF-interacting C-terminal domain (amino acids (aa) 624-947), is unable to promote p100 processing and functions as a potent inhibitor of WT NIK (Lin et al, 1998;Xiao et al, 2001b). Indeed, overexpression of NIK (NIKD) suppresses CD40-, LTbR-and LMP1-mediated NF-kB transactivation and selectively inhibits the processing of p100 in anti-CD40-stimulated cells (Lin et al, 1998;Luftig et al, 2001;Coope et al, 2002). We therefore examined whether NIKD affects LMP1-mediated p100 processing.…”

Tumor necrosis factor receptor-associated factors (TRAFs)

“…At least two di erent kinases, NF-kB-inducing kinase (NIK) and mitogen activated protein kinase/extracellular signal-regulated kinase (ERK) kinase-1 (MEKK1) can phosphorylate IkB kinases (IKKs), which in turn phosphorylate IkB. Although intimal biochemical experiments suggested that TRAF2 mediates NF-kB activation through interaction with NF-kB-inducing kinase (NIK), mice with targeted disruptions of the NIK gene are de®cient in NF-kB activation in response to signals from the LT-b receptor (Luftig et al, 2001), a TRAF3 or TRAF5 pathway, yet retain TNFR1 signals involving TRAF2. Nevertheless, the TRAF2 interaction with NIK may still be a useful model for understanding interactions with other kinases.…”