Ribosomal S6 kinase-1 modulates interleukin-1beta-induced persistent activation of NF-kappaB through phosphorylation of IkappaBbeta.
Activation of NF-kappaB requires the phosphorylation and degradation of its associated inhibitory proteins, IkappaB. Previously, we reported that the extracellular signal-regulated kinase (ERK) is required for IL-1beta to induce persistent activation of NF-kappaB in cultured rat vascular smooth muscle cells (VSMCs). The present study examined the mechanism by which the ERK signaling cascade modulates the duration of NF-kappaB activation. In cultured rat VSMCs, IL-1beta activated ERK and induced degradation of both IkappaBalpha and IkappaBbeta, which was associated with nuclear translocation of both ribosomal S6 kinase (RSK)1 and NF-kappaB p65. RSK1, a downstream kinase of ERK, was associated with an IkappaBbeta/NF-kappaB complex, which was independent of the phosphorylation status of RSK1. Treatment of VSMCs with IL-1beta decreased IkappaBbeta in the RSK1/IkappaBbeta/NF-kappaB complex, an effect that was attenuated by inhibition of ERK activation. Knockdown of RSK1 by small interference RNA attenuated the IL-1beta-induced IkappaBbeta decrease without influencing ether ERK phosphorylation or the earlier IkappaBalpha degradation. By using recombinant wild-type and mutant IkappaBbeta proteins, both active ERK2 and RSK1 were found to directly phosphorylate IkappaBbeta, but only active RSK1 phosphorylated IkappaBbeta on Ser19 and Ser23, two sites known to mediate the subsequent ubiquitination and degradation. In conclusion, in the ERK signaling cascade, RSK1 is a key component that directly phosphorylates IkappaBbeta and contributes to the persistent activation of NF-kappaB by IL-1beta.
Xu
Shanqin
S
Vascular Biology Unit, Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Bayat
Hossein
H
Hou
Xiuyun
X
Jiang
Bingbing
B
D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D046912:Multiprotein Complexes; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*
D004791:Enzyme Inhibitors; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D046912:Multiprotein Complexes; C000606206:Nfkbia protein, rat; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512963:Rps6ka1 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases