Immunology
Protein Kinase C 
Plays Its CARD
John F. Foley
Science Signaling, AAAS, Washington, DC 20005, USA
The C-type lectin receptors (CLRs) are pattern recognition receptors that recognize β-glucan carbohydrates in fungal cell walls. Ligand binding to the CLR Dectin-1 leads to activation of the tyrosine kinase Syk, nuclear factor 
B (NF-B) signaling, and the expression of genes that encode proinflammatory cytokines. Dectin-1–dependent activation of NF-B depends on the cytosolic adaptor protein CARD9. Strasser et al. stimulated mouse bone marrow–derived dendritic cells (BMDCs) with the CLR ligand zymosan to investigate the receptor-proximal signaling events that linked Syk activation to CARD9. Zymosan stimulated the tyrosine phosphorylation of protein kinase C 
(PKC) in a Syk-dependent manner. Stimulation of BMDCs from PKC-deficient mice with zymosan or the Dectin-1–specific ligand curdlan resulted in decreased production of proinflammatory cytokines compared with that of wild-type BMDCs; however, deficiency in other PKC isoforms had no effect. Loss of PKC in BMDCs did not inhibit the phagocytosis of zymosan particles or the Dectin-1–dependent production of reactive oxygen species. PKC-deficient BMDCs showed defective Dectin-1–dependent NF-B activation, and in vitro kinase assays showed that PKC phosphorylated CARD9. Zymosan stimulated the formation in wild-type BMDCs of a complex containing CARD9, its effector protein Bcl-10, and the kinase TAK1, which leads to NF-B activation; however, loss of PKC blocked the assembly of this complex. Infection of wild-type BMDCs with Candida albicans (which is recognized by Dectin-1) resulted in the production of proinflammatory cytokines; however, infected PKC-deficient BMDCs produced decreased amounts of cytokines. PKC-deficient mice infected with C. albicans had lower survival rates than those of infected wild-type mice. Together, these data suggest a specific role for PKC in mediating the Syk-dependent activation of NF-B signaling in response to stimulation of CLRs.
D. Strasser, K. Neumann, H. Bergmann, M. J. Marakalala, R. Guler, A. Rojowska, K.-P. Hopfner, F. Brombacher, H. Urlaub, G. Baier, G. D. Brown, M. Leitges, J. Ruland, Syk kinase-coupled C-type lectin receptors engage protein kinase C- to elicit Card9 adaptor-mediated innate immunity. Immunity 36, 32–42 (2012). [PubMed]
