title: Role of Ca2+/calmodulin-dependent kinase II-IRAK1 interaction in LMP1-induced NF-κB activation.
abstract: We have previously reported that interleukin-1 (IL-1) receptor-associated kinase (IRAK1) is essential for Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1)-induced p65/RelA serine 536 phosphorylation and NF-κB activation but not for IκB kinase α (IKKα) or IKKβ activation (Y. J. Song, K. Y. Jen, V. Soni, E. Kieff, and E. Cahir-McFarland, Proc. Natl. Acad. Sci. U. S. A. 103:2689-2694, 2006, doi:10.1073/pnas.0511096103). Since the kinase activity of IRAK1 is not required for LMP1-induced NF-κB activation, IRAK1 is proposed to function as a scaffold protein to recruit a p65/RelA serine 536 kinase(s) to enhance NF-κB-dependent transcriptional activity. We now report that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) interacts with IRAK1 and is critical for LMP1-induced p65/RelA serine 536 phosphorylation and NF-κB activation. CaMKII bound the death domain of IRAK1 and directly phosphorylated p65/RelA at serine 536 in vitro. Downregulation of CaMKII activity or expression significantly reduced LMP1-induced p65/RelA serine 536 phosphorylation and NF-κB activation. Furthermore, LMP1-induced CaMKII activation and p65/RelA serine 536 phosphorylation were significantly reduced in IRAK1 knockout (KO) mouse embryonic fibroblasts (MEFs). Thus, IRAK1 may recruit and activate CaMKII, which phosphorylates p65/RelA serine 536 to enhance the transactivation potential of NF-κB in LMP1-induced NF-κB activation pathway.
authors.affiliation: Department of Life Science, Gachon University, Seongnam-Si, Kyeonggi-Do, South Korea.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Kim
authors.forename: Sue Yeon
authors.initials: SY
authors.lastname: Lim
authors.forename: Elliott
authors.initials: E
authors.lastname: Kieff
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Song
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D012694:Serine / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014763:Viral Matrix Proteins; D012694:Serine; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2