title: B-cell CLL/lymphoma 10 (BCL10) is required for NF-kappaB production by both canonical and noncanonical pathways and for NF-kappaB-inducing kinase (NIK) phosphorylation.
abstract: B-cell CLL/lymphoma 10 (BCL10), the caspase recruitment domain (CARD)-containing protein involved in the etiology of the mucosa-associated lymphoid tissue (MALT) lymphomas, has been implicated in inflammatory processes in epithelial cells, as well as in immune cells. Experiments in this report indicate that BCL10 is required for activation of nuclear factor (NF)-kappaB by both canonical and noncanonical pathways, following stimulation by the sulfated polysaccharide carrageenan (CGN). In wild type and IkappaB-kinase (IKK)alpha(-/-) mouse embryonic fibroblasts, increases in phospho-IkappaBalpha, nuclear NF-kappaB p65 (RelA) and p50, and KC, the mouse analog of human interleukin-8, were markedly reduced by silencing BCL10 or by exposure to the free radical scavenger Tempol. In IKKbeta(-/-) cells, BCL10 silencing, but not Tempol, reduced the CGN-induced increases in KC, phospho-NF-kappaB-inducing kinase (NIK), cytoplasmic NF-kappaB p100, and nuclear NF-kappaB p52 and RelB, suggesting a BCL10 requirement for activation of the noncanonical pathway. In NCM460 cells, derived from normal, human colonic epithelium, the CGN-induced increases in NF-kappaB family members, p65, p50, p52, and RelB, were inhibited by BCL10 silencing. Although enzyme-linked immunosorbent assay and confocal images demonstrated no change in total NIK following CGN, increases in phospho-NIK in the wild type, IKKbeta(-/-) and IKKalpha(-/-) cells were inhibited by silencing BCL10. These findings indicate an upstream signaling role for BCL10, in addition to its effects on IKKgamma, the regulatory component of the IKK signalosome, and a requirement for BCL10 in both canonical and noncanonical pathways of NF-kappaB activation. Also, the commonly used food additive carrageenan can be added to the short list of known activators of both pathways.
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Alip
authors.initials: A
authors.lastname: Borthakur
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Tyagi
authors.forename: Ravinder
authors.initials: R
authors.lastname: Gill
authors.forename: Mei Ling
authors.initials: ML
authors.lastname: Chen
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Dudeja
authors.forename: Joanne K
authors.initials: JK
authors.lastname: Tobacman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000368:Aged; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D002351:Carrageenan / Q000494:pharmacology; D002460:Cell Line; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency / Q000378:metabolism; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000096:biosynthesis*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; D002351:Carrageenan; D051550:I-kappa B Kinase; D016328:NF-kappa B; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C118591:BCL10 protein, human