The NF-κB Signaling Protein Bcl10 Regulates Actin Dynamics by Controlling AP1 and OCRL-Bearing Vesicles (original) (raw)
Bcl10 can promote survival of antigen-stimulated B lymphocytes
Blood, 2005
To understand the nature of negative responses through the B-cell antigen receptor (BCR), we have screened an expression cDNA library for the ability to block BCR-induced growth arrest and apoptosis in the immature B-cell line, WEHI-231. We isolated multiple copies of full-length, unmutated Bcl10, a signaling adaptor molecule encoded by a gene found to translocate to the immunoglobulin heavy chain (IgH) locus in some mucosa-associated lymphoid tissue (MALT) lymphomas. A conditionally active form of B-cell lymphoma 10 (Bcl10) protected WEHI-231 cells from BCR-induced apoptosis upon activation. Induction of Bcl10 activity caused rapid activation of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK), but not activation of extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein (MAP) kinases. These results support genetic and biochemical experiments that have implicated Bcl10 and its binding partners Carma1 and MALT1 in mediating the ability of the BCR to a...
Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1
Cold Spring Harbor perspectives in biology, 2010
The signaling pathway controlling antigen receptor-induced regulation of the transcription factor NF-kappaB plays a key role in lymphocyte activation and development and the generation of lymphomas. Work of the past decade has led to dramatic progress in the identification and characterization of new players in the pathway. Moreover, novel enzymatic activities relevant for this pathway have been discovered, which represent interesting drug targets for immuno-suppression or lymphoma treatment. Here, we summarize these findings and give an outlook on interesting open issues that need to be addressed in the future.
Leukemia, 2010
Mucosa-associated lymphoid tissue (MALT) lymphoma is characterized by t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/ BCL10-IGH and t(14;18)(q32;q21)/IGH-MALT1, which commonly activate the nuclear factor (NF)-jB pathway. Gastric MALT lymphomas harboring such translocations usually do not respond to Helicobacter pylori eradication, while most of those without translocation can be cured by antibiotics. To understand the molecular mechanism of these different MALT lymphoma subgroups, we performed gene expression profiling analysis of 21 MALT lymphomas (13 translocation-positive, 8 translocation-negative). Gene set enrichment analysis (GSEA) of the NF-jB target genes and 4394 additional gene sets covering various cellular pathways, biological processes and molecular functions have shown that translocation-positive MALT lymphomas are characterized by an enhanced expression of NF-jB target genes, particularly toll like receptor (TLR)6, chemokine, CC motif, receptor (CCR)2, cluster of differentiation (CD)69 and B-cell CLL/lymphoma (BCL)2, while translocationnegative cases were featured by active inflammatory and immune responses, such as interleukin-8, CD86, CD28 and inducible T-cell costimulator (ICOS). Separate analyses of the genes differentially expressed between translocation-positive and -negative cases and measurement of gene ontology term in these differentially expressed genes by hypergeometric test reinforced the above findings by GSEA. Finally, expression of TLR6, in the presence of TLR2, enhanced both API2-MALT1 and BCL10-mediated NF-jB activation in vitro. Our findings provide novel insights into the molecular mechanism of MALT lymphomas with and without translocation, potentially explaining their different clinical behaviors.
Cell, 2001
Translocation t(1;14)(p22;q32) in MALT lymphoma leads to overexpression of Bcl10 and is associated with frameshift mutations causing C-terminal truncations distal of the CARD (Willis et al., 1999; Zhang et al., 1999b). Bcl10 mutations are also found in cases of follic-Institute ular lymphoma and diffuse large B cell lymphoma (Du 620 University Avenue et al., 2000). Toronto, Ontario The human and murine Bcl10 proteins are 91% identi-Canada M5G 2C1 cal. Bcl10 transcripts are expressed ubiquitously and † Ontario Cancer Institute, and Departments throughout development, with high expression levels in of Medical Biophysics and Immunology lymphoid tissues and in the developing central nervous University of Toronto system (CNS) (Costanzo et al., 1999; Koseki et al., 1999; Toronto, Ontario Srinivasula et al., 1999; Thome et al., 1999; Willis et al., Canada M5G 2C1 1999; Yan et al., 1999; Zhang et al., 1999b). The Bcl10 CARD domain mediates self-oligomerization and the C-terminal region of Bcl10, which shows no significant homology to any other known protein, is rich in serine Summary and threonine residues, and can be phosphorylated. (Koseki et al., 1999; Srinivasula et al., 1999). Bcl10, a CARD-containing protein identified from the Transient overexpression of wild-type Bcl10 in cell t(1;14)(p22;q32) breakpoint in MALT lymphomas, has lines both induces apoptosis and activates NF-B (Kobeen shown to induce apoptosis and activate NF-B seki et al., 1999; Thome et al., 1999; Willis et al., 1999; in vitro. We show that one-third of bcl10 Ϫ/Ϫ embryos Yan et al., 1999). Whereas the truncated, tumor-derived developed exencephaly, leading to embryonic lethal-Bcl10 mutants are unable to induce cell death, the CARD ity. Surprisingly, bcl10 Ϫ/Ϫ cells retained susceptibility domain alone is sufficient and necessary for NF-B actito various apoptotic stimuli in vivo and in vitro. Howvation. Apoptosis induced by overexpressed Bcl10 is ever, surviving bcl10 Ϫ/Ϫ mice were severely immunosuppressed by broad-spectrum caspase inhibitors, or deficient and bcl10 Ϫ/Ϫ lymphocytes are defective in by cotransfection of BclxL, X-IAP, cIAP1, c-IAP2, or a antigen receptor or PMA/Ionomycin-induced activadominant-negative version of caspase 9 (Srinivasula et tion. Early tyrosine phosphorylation, MAPK and AP-1 al., 1999; Yan et al., 1999). In addition, cotransfection activation, and Ca 2؉ signaling were normal in mutant of Bcl10 and procaspase 9 results in their direct associalymphocytes, but antigen receptor-induced NF-B action (Yan et al., 1999), suggesting that Bcl10 may particitivation was absent. Thus, Bcl10 functions as a positive pate in the Apaf1/caspase-9 mediated cell death pathregulator of lymphocyte proliferation that specifically way. However, Bcl10 was also found to bind to TRADD, connects antigen receptor signaling in B and T cells and Bcl10-initiated activation of NF-B can be inhibited to NF-B activation. by cotransfection of dominant-negative mutants of TRAF2, NIK, IKK␣, or IB␣ (Costanzo et al., 1999; Koseki Introduction et al., 1999; Srinivasula et al., 1999). To investigate the physiological roles of Bcl10, we The most common type of lymphoma arising in extragenerated bcl10-deficient mice. We demonstrate that nodal sites are B cell lymphomas of mucosa-associated bcl10 is important for neural tube closure and lympholymphoid tissue (MALT lymphomas). Low grade MALT cyte activation. While dispensable for the execution of lymphomas typically develop in the context of prolonged apoptosis, bcl10 is a critical positive regulator of lymreactive lymphoid proliferation at sites of chronic infecphocyte proliferation and a central mediator of NF-B tions such as Helicobacter pylori gastritis, or in autoimactivation in response to antigen receptor signaling in mune disorders (Zucca et al., 2000). The molecular B and T cells. events leading to high grade transformation and antigen-independent growth are still largely unknown. However, chromosomal translocation t(1;14)(p22;q32), is re-Results current in MALT lymphoma and is associated with aggressive disease (Spencer, 1999). Molecular cloning Generation of bcl10 Ϫ/Ϫ Mice of the breakpoint identified a novel gene, Bcl10, which The bcl10 gene was disrupted by homologous recombiis translocated to the immunoglobulin heavy chain locus (Willis et al., 1999; Zhang et al., 1999b). The human Bcl10 nation in murine embryonic stem (ES) cells using stangene encodes a protein of 233 amino acids containing dard procedures ( . Heterozygous an N-terminal caspase recruitment domain (CARD).
Interplay between BCL10, MALT1 and IκBα during T-cell-receptor-mediated NFκB activation
Journal of Cell Science, 2010
T-cell-receptor (TCR) signalling to NFκB requires the assembly of a large multiprotein complex containing the serine/threonine kinase CK1α, the scaffold protein CARMA1, the heterodimer BCL10-MALT1 (the CBM complex) and the IκB kinase complex (IKK). Although the mechanisms regulating recruitment and activation of IKK within the CBM microenvironment have been extensively studied, there is little understanding of how IKK subsequently binds and phosphorylates IκBα, the inhibitor of NFκB, to promote IκBα ubiquitylation and proteasomal degradation. Here, we show that BCL10, MALT1 and IKK inducibly associate with IκBα in a complex that is physically distinct from the early CK1α-CBM signalosome. This IκBα-containing complex probably maturates from the CBM, because siRNA-based knockdown of CARMA1, CK1α and BCL10 hampered its assembly, leading to a reduction in NFκB activation. By contrast, CK1α normally recruited both BCL10 and ubiquitylated species of MALT1 when IκBα levels were reduced. Ho...
Among the genetic abnormalities reported to occur in mucosa-associated lymphoid tissue (MALT) lymphomas, the three translocations t(11;18)(q21;q21), t(1;14)(p22;q32) and t(14;18)(q32;q21) are of particular interest because they appear to be specific for, or at least closely related to this type of B-cell non-Hodgkin's lymphoma. These translocations affect the MALT1 (18q21) and BCL10 (1p22) genes. We retrieved 77 consecutive biopsies of MALT lymphomas (documented with frozen material) over a 10-year period and investigated these cases for the presence of these three translocations with fluorescence in situ hybridisation, along with the immunohistochemical analysis of the intracellular localisation of the BCL10 protein. The above-listed translocations occurred mutually exclusive and were detected in 10, 1 and 3% of the cases, respectively (the latter incidence being much lower than in the previously reported studies by one single group). These genetic rearrangements corresponded well with the aberrant subcellular localisation of the BCL10 protein as found by immunohistochemistry: t(11;18)(q21;q21) and (1;14)(p22;q32) were marked by a, respectively, moderate to strong nuclear BCL10 staining pattern while t(14;18)(q32;q21)-positive MALT lymphomas were characterised by a perinuclear BCL10 staining pattern. This study further supports the close interaction between the MALT1 and BCL10 proteins in the pathogenesis of MALT lymphomas and may indicate that BCL10 immunohistochemistry is a simple technique to identify those MALT lymphoma cases with an underlying genetic aberration.
Journal of Biological Chemistry, 2010
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)-B by both canonical and noncanonical pathways, following stimulation by the sulfated polysaccharide carrageenan (CGN). In wild type and IB-kinase (IKK)␣ ؊/؊ mouse embryonic fibroblasts, increases in phospho-IB␣, nuclear NF-B 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 IKK ؊/؊ cells, BCL10 silencing, but not Tempol, reduced the CGN-induced increases in KC, phospho-NF-B-inducing kinase (NIK), cytoplasmic NF-B p100, and nuclear NF-B 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-B 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, IKK ؊/؊ and IKK␣ ؊/؊ cells were inhibited by silencing BCL10. These findings indicate an upstream signaling role for BCL10, in addition to its effects on IKK␥, the regulatory component of the IKK signalosome, and a requirement for BCL10 in both canonical and noncanonical pathways of NF-B activation. Also, the commonly used food additive carrageenan can be added to the short list of known activators of both pathways.