Functional Characterization of Porcine (Sus scrofa) BCL10


Human BCL10 (hBCL10) protein is a signal transduction molecule originally identified because of its direct involvement in a subset of mucosa-associated lymphoid tissue (MALT) lymphomas, and later recognized as a crucial factor in regulating activation of NF-kB transcription factor following antigen receptor stimulation on lymphocytes. In this study, we characterized the NF-kB inducing activity of porcine BCL10 (pBCL10). pBCL10 oligimerizes, binds to components of the CARMA/ BCL10/MALT1 complex and forms cytoplasmic filaments. Functionally, in human cells pBCL10 is more effective in activating NF-kB compared to hBCL10, possibly due to the lack of carboxy-terminal inhibitory serine residues present in the human protein. Also, depletion experiments carried out through expression of short hairpin RNAs targeting hBCL10 indicate that pBcl10 can functionally replace the human protein and retains its higher NF-kB-inducing property in the absence of hBCL10. Our results contribute useful information on BCL10 protein in pigs, and may help the development of strategies based on the control of the immune response in pigs.

Share and Cite:

Mazzone, P. , Scudiero, I. , Ferravante, A. , Paolucci, M. , D’Andrea, L. , Varricchio, E. , Telesio, G. , Pizzulo, M. , Zotti, T. , Reale, C. , Vito, P. and Stilo, R. (2015) Functional Characterization of Porcine (Sus scrofa) BCL10. Open Journal of Immunology, 5, 64-71. doi: 10.4236/oji.2015.52007.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Willis, T.G., Jadayel, D.M., Du, M.Q., Peng, H., Perry, A.R., et al. (1999) Bcl10 is Involved in t(1;14)(p22;q32) of MALT B Cell Lymphomas and Mutated in Multiple Tumor Types. Cell, 96, 35-45
[2] Zhang, Q., Siebert, R., Yan, M., Hinzmann, B., Cui, X., et al. (1999) Inactivating Mutation and BCL10, a Caspase Recruitment Domain-Containing Gene, in MALT Lymphoma with t(1;14)(p22;q32). Nature Genetics 22, 63-68.
[3] Vito, P. and Stilo, R. (2014) Fifteen Years of BCL10. Immunology Letters, 160, 102-103.
[4] Oeckinghaus, A., Hayden, M.S. and Ghosh, S. (2011) Crosstalk in NF-kappaB Signaling Pathways. Nature Immunology, 12, 695-708.
[5] Vallabhapurapu, S. and Karin, M. (2009) Regulation and Function of NF-kappaB Transcription Factors in the Imune System. Annual Review of Immunology, 27, 693-733.
[6] Ruland, J., Duncan, G.S., Elia, A., del Barco Barrantes, I., Nguyen, L., et al. (2001) Bcl10 is a Positive Regulator of Antigen Receptor-Induced Activation of NF-kappaB and Neural Tube Closure. Cell, 104, 33-42.
[7] Thome, M., Charton, J.E., Pelzer, C. and Hailfinger, S. (2012) Antigen Receptor Signaling to NF-kB via CARMA1, BCL10, and MALT1. Cold Spring Harbor Perspectives in Biology, 2, Article ID: a003004.
[8] Scudiero, I., Vito, P. and Stilo, R. (2014) The Three CARMA Sisters: So Different, So Similar. A Portrait of the Three CARMA Proteins and Their Involvement in Human Disorders. Journal of Cellular Physiology, 229, 990-997.
[9] Stilo, R., Liguoro, D., Di Jeso, B., et al. (2004) Physical and Functional Interaction of CARMA1 and CARMA3 with Ikappa Kinase Gamma-NF-kappaB Essential Modulator. Journal of Biological Chemistry, 279, 34323-34331.
[10] Sun, L., Deng, L., Ea, C.K., Xia, Z.P. and Chen, Z.J. (2004) The TRAF6 Ubiquitin Ligase and TAK1 Kinase Mediate IKK Activation by BCL10 and MALT1 in T lymphocytes. Molecular Cell, 14, 289-301.
[11] Zhou, H.L., Wertz, I., O’Rourke, K., Ultsch, M., Seshagiri, S., et al. (2004) Bcl10 Activates the NF-κB Pathway through Ubiquitination of NEMO. Nature, 427, 167-171.
[12] Huang, J., Ma, G.-J., Sun, N.N., Wu, Z.F., Li X.Y. and Zhao, S.H. (2010) BCL10 as a New Candidate Gene for Immune Response in Pigs: Cloning, Expression and Association Analysis. International Journal of Immunogenetics, 37, 103-110.
[13] Mazzone, P., Scudiero, I., Coccia, E., Ferravante, A., Paolucci, M., et al. (2015) Functional Characterization of a BCL10 Isoform in the Rainbow Trout Oncorhynchus mykiss. FEBS Open Bio, 5, 175-181.
[14] Scudiero, I., Zotti, T., Ferravante, A., Vessichelli, M., Vito, P., et al. (2011) Alternative Splicing of CARMA2/ CARD14 Transcripts Generates Protein Variants with Differential Effect on NF-κB Activation and Endoplasmic Reticulum Stress-Induced Cell Death. Journal of Cellular Physiology, 226, 3121-3131.
[15] Zotti, T., Uva, A., Ferravante, A., Vessichelli, M., Scudiero, I., et al. (2011) TRAF7 Protein Promotes Lys-29-Linked Polyubiquitination of IκB Kinase (IKKγ)/NF-κB Essential Modulator (NEMO) and p65/RelA Protein and Represses NF-κB Activation. Journal of Biological Chemistry, 286, 22924-22933.
[16] Scudiero, I., Zotti, T., Ferravante, A., Vessichelli, M., Reale, C., et al. (2012) Tumor Necrosis Factor (TNF) Receptor- Associated Factor 7 Is Required for TNFα-Induced Jun NH2-Terminal Kinase Activation and Promotes Cell Death by Regulating Polyubiquitination and Lysosomal Degradation of c-FLIP Protein. Journal of Biological Chemistry, 287, 6053-6061.
[17] Stilo, R., Liguoro, D., di Jeso, B., Leonardi, A. and Vito, P. (2003) The Alpha-Chain of the Nascent Polypeptide-Asso- ciated Complex Binds to and Regulates FADD Function. Biochemical and Biophysical Research Communications, 303, 1034-1041.
[18] Costanzo, A., Guet, C. and Vito, P. (1999) c-E10 Is a Caspase-Recruiting Domain-Containing Protein That Interacts with Components of Death Receptors Signaling Pathway and Activates Nuclear Factor-κB. Journal of Biological Che- mistry, 274, 20127-20132.
[19] Guiet, C., Silvestri, E., De Smaele, E., Franzoso, G. and Vito, P. (2002) c-FLIP Efficiently Rescues TRAF-2-/- Cells from TNF-Induced Apoptosis. Cell Death & Differentiation, 9, 138-144.
[20] Wegener, E., Oeckinghaus, A., Papadopoulou, N., Lavitas, L., Schmidt-Supprian, M., et al. (2006) Essential Role for IκB Kinase Beta in Remodeling Carma1-Bcl10-Malt1 Complexes upon T Cell Activation. Molecular Cell, 23, 13-23.
[21] Yoneda, T., Imaizumi, K., Maeda, M., Yui, D., Manabe, T., et al. (2000) Regulatory Mechanisms of TRAF2-Mediated Signal Transduction by Bcl10, a MALT Lymphoma-Associated Protein. Journal of Biological Chemistry, 275, 11114- 11120.
[22] Gaide, O., Martinon, F., Micheau, O., Bonnet, D., Thome, M., et al. (2001) Carma1, a CARD-Containing Binding Partner of Bcl10, Induces Bcl10 Phosphorylation and NF-κB Activation. FEBS Letters, 496, 121-127.
[23] Qiao, Q., Yang, C.H., Zheng, C., Fontán, L., David, L., et al. (2013) Structural Architecture of the CARMA1/Bcl10/ MALT1 Signalosome: Nucleation Induced Filamentous Assembly. Molecular Cell, 51, 766-779.
[24] Guiet, C. and Vito, P. (2000) Caspase Recruitment Domain (CARD)-Dependent Cytoplasmic Filaments Mediate bcl10-Induced NF-kappaB Activation. The Journal of Cell Biology, 148, 1131-40.
[25] Stilo, R., Liguoro, D., Di Jeso, B., Baens, M., Kloo, B., et al. (2004) Physical and Functional Interaction of CARMA1 and CARMA3 with Iκ Kinase Gamma-NF-κB Essential Modulator. Journal of Biological Chemistry, 279, 34323- 34331.
[26] Düwel, M., Welteke, V., Oeckinghaus, A., Baens, M., Kloo, B., et al. (2009) A20 Negatively Regulates T Cell Receptor Signaling to NF-κB by Cleaving Malt1 Ubiquitin Chains. Journal of Immunology, 182, 7718-7728.

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.