p47 negatively regulates IKK activation by inducing the lysosomal degradation of polyubiquitinated NEMO

Yuri Shibata, Masaaki Oyama, Hiroko Kozuka-Hata, Xiao Han, Yuetsu Tanaka, Jin Gohda and Jun-ichiro Inoue ()
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Yuri Shibata: Institute of Medical Science, University of Tokyo, Shirokane-dai
Masaaki Oyama: Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, Shirokane-dai
Hiroko Kozuka-Hata: Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, Shirokane-dai
Xiao Han: Institute of Medical Science, University of Tokyo, Shirokane-dai
Yuetsu Tanaka: Faculty of Medicine, University of the Ryukyus
Jin Gohda: Institute of Medical Science, University of Tokyo, Shirokane-dai
Jun-ichiro Inoue: Institute of Medical Science, University of Tokyo, Shirokane-dai

Nature Communications, 2012, vol. 3, issue 1, 1-13

Abstract: Abstract The persistent or excess activation of NF-κB causes various inflammatory and autoimmune diseases, but the molecular mechanisms that negatively regulate NF-κB activation are not fully understood. Here we show that p47, an essential factor for Golgi membrane fusion, associates with the NEMO subunit of the IκB kinase (IKK) complex upon TNF-α or IL-1 stimulation, and inhibits IKK activation. p47 binds to Lys63-linked and linear polyubiquitin chains, which are conjugated to NEMO upon such stimulation. The binding of p47 to polyubiquitinated NEMO triggers the lysosomal degradation of NEMO, thereby inhibiting IKK activation. The silencing of p47 results in enhanced TNF-α- or IL-1-induced IKK activation, and an increased expression of genes encoding inflammatory mediators. Taken together, our results suggest that p47 is critical for negatively regulating stimulation-induced IKK activation in a manner that is mechanistically distinct from the previously characterized negative regulators, such as A20 and CYLD.

Date: 2012
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DOI: 10.1038/ncomms2068

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