NF-kB signaling has a crucial role in regulating the activation, proliferation and effector functions of lymphocytes in adaptive immune responses. Deregulation of this process results in immunodeficiency, autoimmune diseases, or neoplastic disorders. In the presence of additional co-stimulatory signals, NF-kB is activated by the engagement of TCR with MHC-bound antigen peptides or the interaction of BCR with antigens. The protein kinase C ? (PKC?) of T-cells and PKC? of B-cells are recruited to lipid rafts during antigen-receptor triggering and play key roles in TCR- and BCR-induced NF-kB activation, respectively. The ternary complex of CARMA1 [caspase-recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1, also known as CARD11], Bcl10 (B-cell lymphoma 10) and MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) acts downstream of PKC? and PKC? to induced activation of the IkB kinase (IKK) in both B and T lymphocytes (Figure 1). CARMA1 appears to be constitutively associated with the cytoplasmic membrane. Upon TCR stimulation, CARMA1 is redistributed to the lipid rafts at the immunological synapse to recruit Bcl10 and MALT1 to form the CARMA1-Bcl10-MALT1 (CBM) complex. No structural information is currently available on the CBM complex or its component proteins. In addition, despite having domains that belong to known protein families, CARMA1, Bcl10 and MALT1 exhibit very limited sequence homology to any of the known proteins. To fill this gap, we propose a complete comprehensive structural analysis on the CBM complex, including its assembly mechanisms, conformational changes, enzymatic activities and post-translational modifications. These studies will inevitably provide insights into this important signaling complex.

Public Health Relevance

The proteins in the CBM complex play critical roles in Non-Hodgkin's lymphomas and may be bona fide oncogenes. CARMA1 overexpression has been found in adult T-cell leukemia, primary gastric B-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). In DLBCL, the most common form of non-Hodgkin's lymphoma, missense mutations of CARMA1 have been found at the coiled coil region of CARMA1, which correlate with constitutive NF-kB activation. Chromosomal translocations of both Bcl10 and MALT1 have been found in mucosa-associated lymphoid tissue (MALT) lymphoma. The most frequent chromosomal aberrations in MALT lymphoma are the t(11;18)(q21:q21) and t(14;18)(q32:q21) translocations, which account for about half of all MALT lymphoma. The former translocation creates a fusion protein comprising the BIR domains of cIAP2 and the meta-caspase domain of MALT1 and constitutive NF-kB activation. The t(14;18) translocation results in positioning of the MALT1 genes to the Ig heavy chain locus. Similarly for Bcl10, the t(1;14)(p22:q32) translocation places the Bcl10 to the Ig heavy chain locus. These translocations likely activate NF-kB through MALT1 and Bcl10 overexpression. Collectively, these studies suggest that the CBM complex is an attractive therapeutic target neoplastic disorders of the lymphocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI089882-03
Application #
8260245
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Leitner, Wolfgang W
Project Start
2010-05-01
Project End
2012-06-30
Budget Start
2012-05-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$55,769
Indirect Cost
$22,770
Name
Weill Medical College of Cornell University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Yang, Chenghua; David, Liron; Qiao, Qi et al. (2014) The CBM signalosome: potential therapeutic target for aggressive lymphoma? Cytokine Growth Factor Rev 25:175-83
Qiao, Qi; Yang, Chenghua; Zheng, Chao et al. (2013) Structural architecture of the CARMA1/Bcl10/MALT1 signalosome: nucleation-induced filamentous assembly. Mol Cell 51:766-79
Napetschnig, Johanna; Wu, Hao (2013) Molecular basis of NF-*B signaling. Annu Rev Biophys 42:443-68
Wu, Hao (2013) Higher-order assemblies in a new paradigm of signal transduction. Cell 153:287-92