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

• DOI: 10.1038/ncomms2068
• Publication Date: 2012-09-18T09:43:23Z
• Authors: Yuri Shibata; Masaaki Oyama; Hiroko Kozuka-Hata; Xiao Han; Yuetsu Tanaka; Jin Gohda; Jun-ichiro Inoue
• Keywords: Adenosine Triphosphatases; 0301 basic medicine; 0303 health sciences; NF-kappa B; Nuclear Proteins; Electrophoretic Mobility Shift Assay; Real-Time Polymerase Chain Reaction; Cell Line; I-kappa B Kinase; Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; Jurkat Cells; 03 medical and health sciences; Sf9 Cells; Humans; Immunoprecipitation; Lysosomes; Polyubiquitin; HeLa Cells; Protein Binding

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.