title: Immunoproteasome deficiency modifies the alternative pathway of NFκB signaling.
abstract: Immunoproteasome is a protease abundant in immune cells and also present, albeit at lower concentrations, in cells outside the immune system. Recent evidence supports a novel role for the immunoproteasome in the cellular stress response potentially through regulation of NFκB signaling, which is the primary response to multiple stressors. The current study tests whether the Classical or Alternative Pathways are regulated by immunoproteasome following chronic TNFα exposure in cultured retinal pigment epithelial cells isolated from wild-type mice and mice deficient in one (LMP2, L2) or two (LMP7 and MECL-1, L7M1) immunoproteasome subunits. Assays were performed to assess the expression of NFκB responsive genes, the content and activity of NFκB transcription factors (p65, p50, p52, cRel, RelB), and expression and content of regulatory proteins (IκBα, A20, RPS3). Major findings include distinct differences in expression of NFκB responsive genes in both KO cells. The mechanism responsible for the altered gene expression could not be established for L7M1 since no major differences in NFκB transcription factor content or activation were observed. However, L2 cells exhibited substantially higher content and diminished activation of NFκB transcription factors associated with the Alternative Pathway and delayed termination of the Classical Pathway. These results provide strong experimental evidence supporting a role for immunoproteasome in modulating NFκB signaling.
authors: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors: Marcela
authors: M
authors: Maldonado
authors: Rebecca J
authors: RJ
authors: Kapphahn
authors: Marcia R
authors: MR
authors: Terluk
authors: Neal D
authors: ND
authors: Heuss
authors: Ching
authors: C
authors: Yuan
authors: Dale S
authors: DS
authors: Gregerson
authors: Deborah A
authors: DA
authors: Ferrington
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000032:analysis / Q000276:immunology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology*; D055213:Retinal Pigment Epithelium / Q000166:cytology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex; C490920:Psmb10 protein, mouse