Tumor necrosis factor alpha induction of NF-kappaB requires the novel coactivator SIMPL.
A myriad of stimuli including proinflammatory cytokines, viruses, and chemical and mechanical insults activate a kinase complex composed of IkappaB kinase beta (IKK-beta), IKK-alpha, and IKK-gamma/N, leading to changes in NF-kappaB-dependent gene expression. However, it is not clear how the NF-kappaB response is tailored to specific cellular insults. Signaling molecule that interacts with mouse pelle-like kinase (SIMPL) is a signaling component required for tumor necrosis factor alpha (TNF-alpha)-dependent but not interleukin-1-dependent NF-kappaB activation. Herein we demonstrate that nuclear localization of SIMPL is required for type I TNF receptor-induced NF-kappaB activity. SIMPL interacts with nuclear p65 in a TNF-alpha-dependent manner to promote endogenous NF-kappaB-dependent gene expression. The interaction between SIMPL and p65 enhances p65 transactivation activity. These data support a model in which TNF-alpha activation of NF-kappaB dependent-gene expression requires nuclear relocalization of p65 as well as nuclear relocalization of SIMPL, generating a TNF-alpha-specific induction of gene expression.
Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., MS 4071, Indianapolis, IN 46202-5122, USA.
Hyung-Joo
HJ
Kwon
Erin Haag
EH
Breese
Eva
E
Vig-Varga
Yong
Y
Luo
Younghee
Y
Lee
Mark G
MG
Goebl
Maureen A
MA
Harrington
D000595:Amino Acid Sequence; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D016328:NF-kappa B / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000737:chemistry; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D051996:Transcription Factor RelA; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D019913:Nuclear Localization Signals; D016755:Proto-Oncogene Proteins c-jun; D047888:Receptors, Tumor Necrosis Factor, Type I; C493527:SIMPL protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha