A Novel IκB Protein, IκB-ζ, Induced by Proinflammatory Stimuli, Negatively Regulates Nuclear Factor-κB in the Nuclei

Abstract

The transcription factor nuclear factor-B (NF-B) plays crucial roles in a wide variety of cellular functions and its activity is strictly regulated by cytosolic inhibitors known as IBs. We here report a new member of the IB protein family, IB-, harboring six ankyrin repeats at its carboxyl terminus. IB-mRNA is strongly induced after stimulation by lipopolysaccharide. The induction of IB-is also observed by stimulation with interleukin-1␤ but not by tumor necrosis factor-␣. In contrast to cytosolic IB-␣, -␤, and -⑀, the induced IBlocalizes in the nucleus via its amino-terminal region, which shows no homology with other proteins. Transiently expressed IB-inhibits the NF-B activity without affecting the nuclear translocation of NF-B upon stimulation. The expressed IB-preferentially associates with the NF-B subunit p50 rather than p65 and recombinant IB-proteins inhibit the DNA binding of the p65/p50 heterodimer and the p50/p50 homodimer. Thus, IB-negatively regulates NF-B activity in the nucleus, possibly in order to prevent excessive inflammation. Moreover, transfection of IB-renders cells more susceptible to apoptosis induced by tumor necrosis factor-␣. The proapoptotic activity of IB-further suggests that it might be one of key regulators for inflammation and other biologically relevant processes.

The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-κB target genes by interaction with NFKBIZ

“…A previous report showed that the N-terminal of NFKBIZ was important for nuclear localization (Yamazaki et al, 2001). Our results confirmed these findings, as the N-terminally truncated mutant localized to the cytoplasm.…”

“…NFKBIZ promotes transcription (Kitamura et al, 2000;Motoyama et al, 2005) but may also act as an inhibitor of p50 containing NF-kB complexes (Yamazaki et al, 2001;Totzke et al, 2006). In this study, we report that the MMP1 and LCN2 genes encoding matrix metalloproteinase 1 and lipocalin 2 (a cofactor for MMP9), both involved in extracellular matrix remodeling, are strongly expressed in FUS-DDIT3 carrying cell lines.…”

Molecular modeling‐based evaluation of dual function of IκBζ ankyrin repeat domain in toll‐like receptor signaling

“…In mice, there is no expression of IkBz in the resting state and it is induced by lipopolysaccharide (LPS), interleukin-1 beta (IL-b), peptidoglycan, bacterial lipoprotein, flagellin, and C P G DNA, but not by tumor necrosis factor alpha (TNFa) (Yamazaki et al, 2001;Yamamoto et al, 2004;Motoyama et al, 2005). Conversely, human IkBz expression is strongly induced by TNFa (Totzke et al, 2006).…”

“…Wet lab experiments have shown that human IkBz binds to the p50/p65 heterodimer, while mouse IkBz shows a preference for p50/p50 homodimer. Because it is evident that only C-terminal ARD (452-718) is capable of binding with its partners (Yamazaki et al, 2001;Motoyama et al, 2005;Totzke et al, 2006), we have concentrated solely on the C-terminal ARD in the present study.…”

“…IkBz, which was discovered independently in three laboratories (Kitamura et al, 2000;Haruta et al, 2001;Yamazaki et al, 2001), has a high degree of homology with Bcl-3 and has been described as a regulator of NF-kB. In mice, there is no expression of IkBz in the resting state and it is induced by lipopolysaccharide (LPS), interleukin-1 beta (IL-b), peptidoglycan, bacterial lipoprotein, flagellin, and C P G DNA, but not by tumor necrosis factor alpha (TNFa) (Yamazaki et al, 2001;Yamamoto et al, 2004;Motoyama et al, 2005).…”