A novel IkappaB protein, IkappaB-zeta, induced by proinflammatory stimuli, negatively regulates nuclear factor-kappaB in the nuclei.
The transcription factor nuclear factor-kappaB (NF-kappaB) plays crucial roles in a wide variety of cellular functions and its activity is strictly regulated by cytosolic inhibitors known as IkappaBs. We here report a new member of the IkappaB protein family, IkappaB-zeta, harboring six ankyrin repeats at its carboxyl terminus. IkappaB-zeta mRNA is strongly induced after stimulation by lipopolysaccharide. The induction of IkappaB-zeta is also observed by stimulation with interleukin-1beta but not by tumor necrosis factor-alpha. In contrast to cytosolic IkappaB-alpha, -beta, and -epsilon, the induced IkappaB-zeta localizes in the nucleus via its amino-terminal region, which shows no homology with other proteins. Transiently expressed IkappaB-zeta inhibits the NF-kappaB activity without affecting the nuclear translocation of NF-kappaB upon stimulation. The expressed IkappaB-zeta preferentially associates with the NF-kappaB subunit p50 rather than p65 and recombinant IkappaB-zeta proteins inhibit the DNA binding of the p65/p50 heterodimer and the p50/p50 homodimer. Thus, IkappaB-zeta negatively regulates NF-kappaB activity in the nucleus, possibly in order to prevent excessive inflammation. Moreover, transfection of IkappaB-zeta renders cells more susceptible to apoptosis induced by tumor necrosis factor-alpha. The proapoptotic activity of IkappaB-zeta further suggests that it might be one of key regulators for inflammation and other biologically relevant processes.
Yamazaki
S
S
Department of Molecular and Cellular Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Muta
T
T
Takeshige
K
K
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism*; D017931:DNA Primers; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D017386:Sequence Homology, Amino Acid
D017931:DNA Primers; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D020033:Protein Isoforms; D012333:RNA, Messenger