Abstract
The nuclear factor (NF)-κB family of transcription factors regulates diverse cellular functions, including inflammation, oncogenesis and apoptosis. It was reported that A20 plays a critical role in the termination of NF-κB signaling after activation. Previously, we showed that Ymer interacts and collaborates with A20, followed by degradation of receptor-interacting protein (RIP) and attenuation of NF-κB signaling. Here we show the function of Ymer in regulation of several signaling pathways including NF-κB on the basis of results obtained by using Ymer transgenic (Ymer Tg) mice. Ymer Tg mice exhibited impaired immune responses, including NF-κB and mitogen-activated protein kinase (MAPK) activation, cell proliferation and cytokine production, to tumor necrosis factor (TNF)-α, polyI:C or lipopolysaccharide (LPS) stimulation. Ymer Tg mice were more resistant to LPS-induced septic shock than wild-type mice. Transgene of Ymer inhibited the onset of glomerulonephritis in lpr/lpr mice as an autoimmune disease model. In contrast to the inflammatory immune response to LPS, Fas-mediated cell death was strongly induced in liver cells of Ymer Tg mice in which Ymer is abundantly expressed. These findings suggest that Ymer acts as a regulator downstream of several receptors and that Ymer functions as a positive or negative regulator in a signaling pathway-dependent manner.
Highlights
Nuclear factor (NF)-κB is a ubiquitously expressed transcription factor that induces the expression of target genes and regulates diverse cellular functions including inflammation, immunity, cell growth and apoptosis in response to various stimuli [1]
The cleavage product of poly(ADPribose) polymerase (PARP) at 50 kDa, which has been reported as evidence of necrotic cell death [12], was observed in WT mice with LPS or TNFα treatment, but cleavage products were not observed in either line of Ymer transgenic (Ymer Tg) mice (Figure 2A). These findings suggest that overexpression of Ymer causes decrease in the NFκB signal via TLR4 or tumor necrosis factor receptor (TNFR) in hepatocytes as well as splenocytes
Because NF-κB activation is inhibited in Ymer Tg mice, negative feedback to downregulate receptorinteracting protein (RIP) may be suppressed. These findings suggest that overexpression of Ymer protein in splenocytes and hepatocytes causes impaired response via TNFR and TLR4 and that negative feedback after NF-κB activation is inhibited in Ymer Tg mice
Summary
Nuclear factor (NF)-κB is a ubiquitously expressed transcription factor that induces the expression of target genes and regulates diverse cellular functions including inflammation, immunity, cell growth and apoptosis in response to various stimuli [1]. NF-κB is an important molecule downstream of the tumor necrosis factor receptor (TNFR) and Toll-like receptor (TLR). Tumor necrosis factor (TNF)-α stimulation results in recruitment of receptorinteracting protein (RIP) to the intracellular region of TNFR, and RIP undergoes lysine (K) 63-linked polyubiquitination by ubiquitin-conjugating enzeme 13 (Ubc13)/ubiquitin-conjugating enzyme E2 variant 1 (Uev1) A and TNFRassociated factor 2 (TRAF2) as E2 and E3, respectively. The K63-linked polyubiquitin chain on RIP activates transforming growth factor (TGF)-β–associated kinase (TAK)/TAK1 binding protein (TAB) kinase complex. Activated TAK/TAB complex phosphorylates and activates the IκB kinase (IKK) complex, which consists of IKKα, IKKβ and IKKγ/Nemo. Activated IKKβ phosphorylates IκB, and phosphorylated IκB is recognized and ubiquitinated by a ubiquitin ligase complex, SCFFbw (Skp1-Cul1-F-box complex containing Fbw1), followed by degradation of IκB via a proteasomedependent pathway and activation of NF-κB [2,3]
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