Regulation of genes for several lymphokines depend on a 10 bp DNA sequence termed kappaB. This sequence is bound by a family of protein factors related to the Rel oncogene. The prototype transcription complex binding to the sequence, termed NF-kB, is a heterodimer between a P50 DNA binding protein and a P65 (RelA) activation protein that is typically sequestered in the cytoplasm by a protein called I-kB. Following certain types of stimulation to the cell, a specific protein kinase complex called I-kB kinase causes the phosphorylation of I-kB followed by it's ubiquitination and degradation. Among the stimuli that can release NF-kB is the triggering of the T cell receptor (TCR) or B cell receptor (BCR) by antigen during an immune response. We have discovered a rare clinical condition of immunodeficiency and loss of lymphocyte homeostasis due to an inherited genetic deficiency of caspase-8. Remarkably, our studies revealed that the immunodeficiency was caused by a defect in NF-kB induction in lymphocytes following antigen activation. In particular, we found that caspase-8 played a direct role in physically linking the membrane-associated protein complex containing the Carma 1, MALT 1, and the Bcl-10 proteins to the I-kB kinase complex. Furthermore, the proteolytic enzyme activity of caspase-8 appears to be crucial for it to convey the activation signal. Precisely how this occurs, especially the identity of the hypothetical proteolytic substrate of caspase-8, is under investigation. Additional examples of caspase-8 deficiency are being sought in the human population to understand the full clinical and biochemical manifestations of this genetic defect.? While studying the induction of NF-kB in lymphocytes, we have found a third component of the complex which has proved to be crucial to the gene induction capabilities of this transcription factor. The novel component associates with critical subunits of the complex and elimination of the third component potently inhibits the capability of NF-kB to mediate gene induction despite the fact that it has no effect on shuttling of the transcription complex from the cytoplasm to the nucleus. Further biochemical characterization of the third component, which we provisionally named A-kB for """"""""activator of kB"""""""", is presently being carried out. We are also attempting to identify inhibitors of this component, since inhibition of NF-kB is a prime therapeutic target for number of inflammatory and degenerative conditions. Inhibition of NF-kB may also be useful for various infectious diseases involving pathogens, such as HIV, that utilize this factor for their life cycle or pathogenic effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000565-10
Application #
7300512
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Bidere, Nicolas; Ngo, Vu N; Lee, Jeansun et al. (2009) Casein kinase 1alpha governs antigen-receptor-induced NF-kappaB activation and human lymphoma cell survival. Nature 458:92-6
Su, Helen C; Lenardo, Michael J (2008) Genetic defects of apoptosis and primary immunodeficiency. Immunol Allergy Clin North Am 28:329-51, ix
Lemmers, Benedicte; Salmena, Leonardo; Bidere, Nicolas et al. (2007) Essential role for caspase-8 in Toll-like receptors and NFkappaB signaling. J Biol Chem 282:7416-23
Wan, Fengyi; Anderson, D Eric; Barnitz, Robert A et al. (2007) Ribosomal protein S3: a KH domain subunit in NF-kappaB complexes that mediates selective gene regulation. Cell 131:927-39
Bidere, Nicolas; Snow, Andrew L; Sakai, Keiko et al. (2006) Caspase-8 regulation by direct interaction with TRAF6 in T cell receptor-induced NF-kappaB activation. Curr Biol 16:1666-71
Bidere, Nicolas; Su, Helen C; Lenardo, Michael J (2006) Genetic disorders of programmed cell death in the immune system. Annu Rev Immunol 24:321-52
Su, Helen; Bidere, Nicolas; Zheng, Lixin et al. (2005) Requirement for caspase-8 in NF-kappaB activation by antigen receptor. Science 307:1465-8