IL-1 receptor-associated kinase 1 is critical for latent membrane protein 1-induced p65/RelA serine 536 phosphorylation and NF-kappaB activation.
Epstein-Barr virus latent infection integral membrane protein 1 (LMP1) mimics a constitutively active TNF receptor (TNFR). LMP1 has two C-terminal cytosolic domains, transformation effector sites (TES)1 and -2, that engage TNFR-associated factors (TRAFs) and the TNFR-associated death domain protein, respectively, and activate NF-kappaB. NF-kappaB activation is critical for Epstein-Barr virus-infected lymphoblast survival. TES1- and TES2-mediated NF-kappaB activations are IL-1 receptor-associated kinase 1 (IRAK1)-dependent. Because IRAK1 is upstream of TRAF6 in IL-1 activation of NF-kappaB, the potential role of IRAK1 in LMP1-mediated NF-kappaB activation through TRAF6 and inhibitor of kappaB (IkappaB) kinase (IKK) was initially investigated. Surprisingly, LMP1 expression activated TRAF6 ubiquitination, IKKbeta induction of IkappaB alpha phosphorylation, and p65 nuclear translocation in both WT and IRAK1-deficient I1A 293 cells. LMP1 also induced IKK alpha-mediated p100 processing and p52 nuclear localization in WT and IRAK1-deficient I1A 293 cells. Further, LMP1 TES1 and TES2 induced p65, p50, and p52 NF-kappaB DNA binding in WT and IRAK1-deficient I1A 293 cells. However, LMP1 induced p65/RelA S536 phosphorylation only in WT 293 cells or in IRAK1 kinase point mutant reconstituted I1A 293 cells but not in IRAK1-deficient I1A 293 cells. IRAK1 was also required for LMP1 activation of p38, one of the kinases that can mediate p65/RelA S536 phosphorylation and activate NF-kappaB-dependent transcription. Thus, the critical IRAK1 role in LMP1-induced NF-kappaB activation is in mediating p65/RelA S536 phosphorylation through an effect on p38 or other p65 S536 kinases.
Department of Medicine, Harvard Medical School, Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA.
Yoon-Jae
YJ
Song
Kai-Yu
KY
Jen
Vishal
V
Soni
Elliott
E
Kieff
Ellen
E
Cahir-McFarland
D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport; D012694:Serine / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D051996:Transcription Factor RelA; D025801:Ubiquitin; D014763:Viral Matrix Proteins; D012694:Serine; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases