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.

Abstract

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.

• Authors: Liza Ho, R Eric Davis, Béatrice Conne, Richard Chappuis, Margaret Berczy, Paulette Mhawech, Louis M Staudt, Juerg Schwaller
• Journal: Blood (Blood) Vol. 105 Issue 7 Pg. 2891-9 (Apr 01 2005) ISSN: 0006-4971 [Print] United States
• PMID: 15598810 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• API2-MALT1 fusion protein, human
• CD40 Antigens
• NF-kappa B
• Neoplasm Proteins
• Oncogene Proteins, Fusion
• fas Receptor
• Protein Serine-Threonine Kinases
• CHUK protein, human
• I-kappa B Kinase
• IKBKB protein, human
• IKBKE protein, human
• Caspases
• MALT1 protein, human
• Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein

Topics

• Apoptosis (immunology)
• B-Lymphocytes (cytology, metabolism)
• CD40 Antigens (metabolism)
• Caspases
• Cell Division (immunology)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic (immunology)
• Humans
• I-kappa B Kinase
• Lymphoma, B-Cell
• Lymphoma, B-Cell, Marginal Zone (genetics, metabolism)
• Membrane Microdomains (immunology)
• Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
• NF-kappa B (metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Oncogene Proteins, Fusion (genetics, metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Signal Transduction (immunology)
• fas Receptor (metabolism)