HOIL-1L Interacting Protein HOIP as an NF-κB Regulating Component of the CD40 Signaling ComplexReport as inadecuate




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The tumor necrosis factor receptor TNFR superfamily mediates signals critical for regulation of the immune system. One family member, CD40, is important for the efficient activation of antibody-producing B cells and other antigen-presenting cells. The molecules and mechanisms that mediate CD40 signaling are only partially characterized. Proteins known to interact with the cytoplasmic domain of CD40 include members of the TNF receptor-associated factor TRAF family, which regulate signaling and serve as links to other signaling molecules. To identify additional proteins important for CD40 signaling, we used a combined stimulation-immunoprecipitation procedure to isolate CD40 signaling complexes from B cells and characterized the associated proteins by mass spectrometry. In addition to known CD40-interacting proteins, we detected SMAC-DIABLO, HTRA2-Omi, and HOIP-RNF31-PAUL-ZIBRA. We found that these previously unknown CD40-interacting partners were recruited in a TRAF2-dependent manner. HOIP is a ubiquitin ligase capable of mediating NF-κB activation through the ubiquitin-dependent activation of IKKγ. We found that a mutant HOIP molecule engineered to lack ubiquitin ligase activity inhibited the CD40-mediated activation of NF-κB. Together, our results demonstrate a powerful approach for the identification of signaling molecules associated with cell surface receptors and indicate an important role for the ubiquitin ligase activity of HOIP in proximal CD40 signaling.



Author: Bruce S. Hostager , Daniel K. Fox, Douglas Whitten, Curtis G. Wilkerson, Betty A. Eipper, Victor P. Francone, Paul B. Rothman, Jo

Source: http://plos.srce.hr/



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