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J. Biol. Chem., Vol. 280, Issue 2, 1217-1223, January 14, 2005

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Role for Protein Kinase C (PKC) in TCR/CD28-mediated Signaling through the Canonical but Not the Non-canonical Pathway for NF-B Activation^*

Yingqiu Li¶, Caitlin E. Sedwick¶, Junru Hu, and Amnon Altman||

From the Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121 and the State Key Laboratory of Biocontrol, College of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China

NF-B is a family of essential transcription factors involved in both embryonic development and inflammatory responses of the immune system. NF-B can be activated by two pathways, i.e. the canonical (NF-B1) pathway, which acts through the catalytic components of the IB kinase complex and leads to IB phosphorylation, degradation, and subsequent NF-B nuclear translocation, or the non-canonical (NF-B2) pathway, which involves NF-B-induced kinase-dependent proteolytic processing of p100/p52 to yield translocation-competent p52-containing NF-B complexes. We examined the relative roles of the NF-B1 and NF-B2 pathways in TCR/CD28 costimulation. We found that TCR/CD28 costimulation activates the canonical but not the non-canonical NF-B pathway and that the serine/threonine kinase protein kinase C (PKC) is essential for TCR/CD28-mediated canonical NF-B 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 IB, IB, and IB degradation, and PKC is required for IB and IB but not IB degradation. PKC acts solely within the canonical pathway to activate NF-B, and PKC deficiency impacts upon p100/p52 processing in a manner that is independent of NF-B-induced kinase.

Received for publication, August 18, 2004 , and in revised form, November 4, 2004.

^* This work was supported by National Institutes of Health Grants CA35299 and AI49888 (to A. A.) and AI51909 (to C. E. S.). This is publication 669 from the La Jolla Institute for Allergy and Immunology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Div. Of Cell Biology, La Jolla Inst. for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121. Tel.: 858-558-3527; Fax: 858-558-3526; E-mail: amnon{at}liai.org.

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