Abstract
The non-canonical NF-κB pathway is crucial for the immune system. A critical event in activation of the non-canonical pathway is the attenuation of NF-κB-inducing kinase (NIK) degradation, which is promoted by continuous polyubiquitination of NIK catalyzed by the NIK ubiquitin-ligase complex composed of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2), TNF receptor-associated factor 2 (TRAF2), and TRAF3. However, the molecular mechanism of stimulation-dependent NIK stabilization remains poorly understood. Here, we show that A20, a ubiquitin-editing enzyme, promotes efficient activation of the non-canonical pathway independent of its catalytic activity. A20 directly binds to cIAP1 through the seventh zinc finger of A20, resulting in dissociation of the TRAF2/TRAF3 interaction, thereby inactivating the ligase complex to stabilize NIK. Given that A20 negatively regulates the canonical pathway, A20 is likely involved in the molecular switch that promotes the transition from canonical to non-canonical activation for proper control of the immune system.
Highlights
Correspondence and requests for materials should be addressed to Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
A critical event in activation of the non-canonical pathway is the attenuation of nuclear factor-kB (NF-kB)-inducing kinase (NIK) degradation, which is promoted by continuous polyubiquitination of NIK catalyzed by the NIK ubiquitin-ligase complex composed of cellular inhibitor of apoptosis protein 1 and 2, tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2), and TRAF3
The non-canonical pathway, which is required for lymphoid organogenesis, is activated by stimulation by lymphotoxin-b receptor (LTbR), CD40, receptor activator of NF-kB (RANK), fibroblast growth factor-inducible 14 (Fn14), or B cell activating factor belonging to TNF family receptor (BAFFR)
Summary
Correspondence and requests for materials should be addressed to Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan. The canonical pathway is activated by cytokines such as tumor necrosis factor (TNF)-a and interleukin (IL)-1 and bacterial products and plays a critical role in the expression of inflammatory cytokines and inhibition of apoptosis Stimulation with these ligands leads to the activation of the IkB kinase (IKK) complex, which consists of the catalytic subunits IKKa and IKKb and the regulatory subunit NF-kB essential modulator (NEMO). The non-canonical pathway, which is required for lymphoid organogenesis, is activated by stimulation by lymphotoxin-b receptor (LTbR), CD40, receptor activator of NF-kB (RANK), fibroblast growth factor-inducible 14 (Fn14), or B cell activating factor belonging to TNF family receptor (BAFFR) This pathway involves activation of the IKKa homodimer, which phosphorylates the C-terminal domain of p100 and targets it to proteasome-dependent processing to generate p52, allowing the p52/ RelB complex to enter the nucleus and activate target genes[3,4]. We show, for the first time, that A20 functions as a positive regulator of the noncanonical pathway by promoting the stimulation-dependent stabilization of NIK
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