Requirement for Caspase-8 in NF-κB Activation by Antigen Receptor

Science, 307:1465-1468, 2005

Speaker: 江承堯                              Time: 13:00~14:00 05/25/2005

Commentator: 林秋烽 博士                     Place: Room 601

Abstract:

    Caspases, which are cysteine proteases, are involved in cell apoptosis pathway. Recent study show during T cell proliferation, differentiation, or activation, caspase may play a central role in these pathways. Here authors found T cell activation was associated with caspase.¹ Some questions from antigen receptor to NF-kB remain unresolved. One of the questions is how CBM (CARMA1, Bcl10, MALT1) complex interacts with IKK (IkB Kinase).² Author used zVAD, a panel caspase inhibitor, to treat human primary T cells and confirmed that caspase was involved in antigen receptor-induced pathway. In pervious study, they demonstrated that caspase-8 deficiency in human might lead to immunodeficiency.³ In caspase-8 deficient Jurkat T cells, I9.2, NF-kB did not translocate into the nucleus after antigen receptor stimulation, but not in parental A3 cell line. In caspase-8 deficient patients, NF-kB also failed to translocate into the nucleus after antigen receptor stimulation, no matter in T, B, or NK cells. After stimulating antigen receptor, amount of phospholated IKK and IkB were increased in parental A3 cell line in 10 minutes, but not in I9.2 cells. This experiment showed that caspase-8 played an upstream role of IKK activation. In immunoprecipitation experiment, the requirement of caspase-8 for the forming of CBM-IKK complex was demonstrated after antigen receptor stimulation. Taken together, during antigen receptor stimulation, caspase-8 is required for CBM complex and then caused NF-kB activation.

References:

1.      Helen Su, et al. Requirement for caspase-8 in NF-kB activation by antigen receptor. Science 307:1465-1468, 2005

2.      Peter C. Lucas, et al. Bcl10 and MALT1, independent targets of chromosomal translocation in MALT lymphoma, cooperate in a novel NF-kB signaling pathway.

 J. Biol. Chem. 276:19012-19019, 2001

3.  Hyung J. Chun, et al. Pleiotropic defects in lymphocyte activation caused by caspase-8         

   mutations lead to human immunodeficiency. Nature 419:395-399, 2002