MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-kappa B-dependent proliferative advantage and resistance against FAS-induced cell death in B cells.
The most frequently recurring translocations in mucosa-associated lymphoid tissue (MALT) B-cell non-Hodgkin lymphoma, t(11;18)(q21;q21) and t(14;18)(q32; q21), lead to formation of an API2-MALT1 fusion or IgH-mediated MALT1 overexpression. Various approaches have implicated these proteins in nuclear factor kappaB (NF-kappa B) signaling, but this has not been shown experimentally in human B cells. Immunohistochemistry showed that MALT1 is predominantly expressed in normal and malignant germinal center B cells, corresponding to the differentiation stage of MALT lymphoma. We expressed MALT1 and apoptosis inhibitor-2 API2/MALT1 in human B-cell lymphoma BJAB cells and found both transgenes in membrane lipid rafts along with endogenous MALT1 and 2 binding partners involved in NF-kappa B signaling, B-cell lymphoma 10 (BCL10) and CARMA1 (caspase recruitment domain [CARD]-containing membrane-associated guanylate kinase [MAGUK] 1). API2-MALT1 and exogenous MALT1 increased constitutive NF-kappa B activity and enhanced I kappa B kinase (IKK) activation induced by CD40 stimulation. Both transgenes protected BJAB cells from FAS (CD95)-induced death, consistent with increases in NF-kappa B cytoprotective target gene expression, and increased their proliferation rate. Expression of a dominant-negative I kappa B alpha mutant showed that these survival and proliferative advantages are dependent on elevated constitutive NF-kappa B activity. Our findings support a model in which NF-kappa B signaling, once activated in a CD40-dependent immune response, is maintained and enhanced through deregulation of MALT1 or formation of an API2-MALT1 fusion.
Ho
Liza
L
Department of Clinical Pathology, Geneva University Hospital, Centre Medical Universitaire, Geneva, Switzerland.
Davis
R Eric
RE
Conne
Béatrice
B
Chappuis
Richard
R
Berczy
Margaret
M
Mhawech
Paulette
P
Staudt
Louis M
LM
Schwaller
Juerg
J
D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism*; D020169:Caspases; D002455:Cell Division / Q000276:immunology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase; D016393:Lymphoma, B-Cell; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics / Q000378:metabolism*; D021962:Membrane Microdomains / Q000276:immunology; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D019014:fas Receptor / Q000378:metabolism
C415943:API2-MALT1 fusion protein, human; D019013:CD40 Antigens; D016328:NF-kappa B; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D019014:fas Receptor; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein