Role for protein kinase Ctheta (PKCtheta) in TCR/CD28-mediated signaling through the canonical but not the non-canonical pathway for NF-kappaB activation.
NF-kappaB is a family of essential transcription factors involved in both embryonic development and inflammatory responses of the immune system. NF-kappaB can be activated by two pathways, i.e. the canonical (NF-kappaB1) pathway, which acts through the catalytic components of the IkappaB kinase complex and leads to IkappaB phosphorylation, degradation, and subsequent NF-kappaB nuclear translocation, or the non-canonical (NF-kappaB2) pathway, which involves NF-kappaB-induced kinase-dependent proteolytic processing of p100/p52 to yield translocation-competent p52-containing NF-kappaB complexes. We examined the relative roles of the NF-kappaB1 and NF-kappaB2 pathways in TCR/CD28 costimulation. We found that TCR/CD28 costimulation activates the canonical but not the non-canonical NF-kappaB pathway and that the serine/threonine kinase protein kinase C (PKC) is essential for TCR/CD28-mediated canonical NF-kappaB activation in T cells. Importantly, TCR/CD28 costimulation induces higher p52 protein levels in T cells, but this effect is secondary to enhanced de novo synthesis of p100, not to enhanced processing of extant p100; PKC deficiency impairs signal-dependent p52 accumulation because of defects in p100 production. Finally, we found that TCR/CD28 costimulation induces IkappaBalpha, IkappaBbeta, and IkappaBepsilon degradation, and PKC is required for IkappaBalpha and IkappaBepsilon but not IkappaBbeta degradation. PKC acts solely within the canonical pathway to activate NF-kappaB, and PKC deficiency impacts upon p100/p52 processing in a manner that is independent of NF-kappaB-induced kinase.
Li
Yingqiu
Y
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
Sedwick
Caitlin E
CE
Hu
Junru
J
Altman
Amnon
A
D021581:Active Transport, Cell Nucleus; D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism*; D002460:Cell Line; D020672:I-kappa B Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit; D011401:Promoter Regions, Genetic / Q000235:genetics; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D018106:CD28 Antigens; D020672:I-kappa B Proteins; D007527:Isoenzymes; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D017346:Protein Serine-Threonine Kinases; D011948:Receptors, Antigen, T-Cell; D000097782:NF-kappaB-Inducing Kinase; C489593:Prkcq protein, mouse