Nuclear IKKbeta is an adaptor protein for IkappaBalpha ubiquitination and degradation in UV-induced NF-kappaB activation.
Proinflammatory cytokines activate NF-kappaB using the IkappaB kinase (IKK) complex that phosphorylates inhibitory proteins (IkappaBs) at N-terminal sites resulting in their ubiquitination and degradation in the cytoplasm. Although ultraviolet (UV) irradiation does not lead to IKK activity, it activates NF-kappaB by an unknown mechanism through IkappaBalpha degradation without N-terminal phosphorylation. Here, we describe an adaptor function of nuclear IKKbeta in UV-induced IkappaBalpha degradation. UV irradiation induces the nuclear translocation of IkappaBalpha and association with IKKbeta, which constitutively interacts with beta-TrCP through heterogeneous ribonucleoprotein-U (hnRNP-U) leading to IkappaBalpha ubiquitination and degradation. Furthermore, casein kinase 2 (CK2) and p38 associate with IKKbeta and promote IkappaBalpha degradation by phosphorylation at C-terminal sites. Thus, nuclear IKKbeta acts as an adaptor protein for IkappaBalpha degradation in UV-induced NF-kappaB activation. NF-kappaB activated by the nuclear IKKbeta adaptor protein suppresses anti-apoptotic gene expression and promotes UV-induced cell death.
Tsuchiya
Yoshihiro
Y
Laboratory of Biomedical Chemistry, Department of Molecular Medical Science, Graduate School of Biomedical Science, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.
Asano
Tomoichiro
T
Nakayama
Keiko
K
Kato
Tomohisa
T
Karin
Michael
M
Kamata
Hideaki
H
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D047390:Casein Kinase II / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D034722:Heterogeneous-Nuclear Ribonucleoprotein U / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000528:radiation effects*; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D054875:Ubiquitination; D014466:Ultraviolet Rays; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D034722:Heterogeneous-Nuclear Ribonucleoprotein U; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D044844:beta-Transducin Repeat-Containing Proteins; D000072000:NF-KappaB Inhibitor alpha; D047390:Casein Kinase II; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases