title: The p97-UFD1L-NPL4 protein complex mediates cytokine-induced IκBα proteolysis.
abstract: IκBα is an inhibitor of NF-κB, a family of transcription factors that transactivate genes related to inflammation. Upon inflammatory stimuli, IκBα is rapidly degraded via the ubiquitin-proteasome pathway. While it is very clear that the SCF(β-TRCP) ubiquitin ligase ubiquitinates IκBα upon stimulation, little is known about the postubiquitinational events of IκBα proteolysis. Here, we report that p97, a valosin-containing protein (also called VCP), plays an essential role in the postubiquitinational regulation of IκBα turnover after tumor necrosis factor alpha (TNF-α) or interleukin-1β (IL-1β) treatment. The ATPase activity of p97 is essential for its role in IκBα proteolysis. Moreover, we found that UFD1L and NPL4, two cofactors of p97, assist p97 to control the postubiquitinational regulation of IκBα. The p97-UFD1L-NPL4 protein complex specifically associates with ubiquitinated IκBα via the interactions between p97 and the SCF(β-TRCP) ubiquitin ligase and between the polyubiquitin binding domain of UFD1L and polyubiquitinated IκBα. Furthermore, we observed that the postubiquitinational regulation of IκBα by the p97-UFD1L-NPL4 complex is important for NF-κB activation under stimuli.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Ju-Mei
authors.initials: JM
authors.lastname: Li
authors.forename: Hongyu
authors.initials: H
authors.lastname: Wu
authors.forename: Wenzheng
authors.initials: W
authors.lastname: Zhang
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.forename: Jianping
authors.initials: J
authors.lastname: Jin
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016207:Cytokines / Q000494:pharmacology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D000072000:NF-KappaB Inhibitor alpha; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D034622:RNA Interference; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; C000606204:NFKBIA protein, human; C514112:NPLOC4 protein, human; D009687:Nuclear Proteins; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; C491497:UFD1 protein, human; D000072000:NF-KappaB Inhibitor alpha; D044843:SKP Cullin F-Box Protein Ligases; D000251:Adenosine Triphosphatases; C404942:p97 ATPase