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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK
Pathogenesis Abstract 18
Activation of NF-κB by KSHV K15 involves recruitment of NIK (NF-κB inducing
kinase)
Anika Hävemeier, Macel Pietrek and Thomas F. Schulz
Institute of Virology, Medical School Hannover, Hannover, Germany
Abstract
ORF K15 is the positional homologue of EBV LMP2A. Like LMP2A, the K15 protein
contains 12 predicted transmembrane and a cytoplasmic domain involved in signaling.
The cytoplasmic domain interacts with several cellular proteins, including TRAF and Src
kinases, and activates NF-kB as well as the MAPKs c-Jun-N-terminal kinase (JNK) and
extracellular signal-regulated kinase (Erk). Mutation of tyrosine 481 in the cytoplasmic
tail of K15 (K15 Y 481 F) abolishes the ability of K15 to induce these pathways.
Activation of NF-kB by several stimuli occurs via two distinct pathways: the classical
(canonical) or the alternative (noncanonical) pathway. We found that K15 induces the
alternative NF-kB pathway via NIK, leading to the processing of p100 and the
translocation of p52 into the nucleus. Transfection of a dominant negative NIK and NIK
siRNA decreases the K15 mediated induction of NF-kB, shown by western blot analysis or
luciferase reporter experiments. Using alanin scanning mutants the binding site for NIK
localised to six aminoacids near the last transmembrane domain of K15. NIK-binding
deficient K15 mutants show a decreased NF-kB activation, but appear to retain the ability
to activate other K15-induced promoters.
Direct recruitment of NIK represents a novel way for a viral protein to activate NF-kB. In
activating NF-kB via NIK, KSHV K15 shows functional similarities to the Lymphotoxin
beta-receptor, rather than the B-cell receptor, whose function is thought to be mimicked
by EBV LMP2A.
Presenting author Email: haevemeier.anika@mh-hannover.de
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