Syk Kinase-Coupled C-type Lectin Receptors Engage Protein Kinase C-δ to Elicit Card9 Adaptor-Mediated Innate Immunity

Abstract

SummaryC-type lectin receptors (CLRs) that couple with the kinase Syk are major pattern recognition receptors for the activation of innate immunity and host defense. CLRs recognize fungi and other forms of microbial or sterile danger, and they induce inflammatory responses through the adaptor protein Card9. The mechanisms relaying CLR proximal signals to the core Card9 module are unknown. Here we demonstrated that protein kinase C-δ (PKCδ) was activated upon Dectin-1-Syk signaling, mediated phosphorylation of Card9 at Thr231, and was responsible for Card9-Bcl10 complex assembly and canonical NF-κB control. Prkcd−/− dendritic cells, but not those lacking PKCα, PKCβ, or PKCθ, were defective in innate responses to Dectin-1, Dectin-2, or Mincle stimulation. Moreover, Candida albicans-induced cytokine production was blocked in Prkcd−/− cells, and Prkcd−/− mice were highly susceptible to fungal infection. Thus, PKCδ is an essential link between Syk activation and Card9 signaling for CLR-mediated innate immunity and host protection.

The Unfolded Protein Response and the Phosphorylations of Activating Transcription Factor 2 in the trans-Activation of il23a Promoter Produced by β-Glucans

“…Because ATF2 is activated by phosphorylations dependent on PKC and MAPK activities, it seems a likely target of dectin-1 signaling. The correlation between inhibition of Thr(P)-71-ATF2 binding and blunting of il23a mRNA expression in response to PKC inhibitors can be explained by the upstream position of this kinase, in particular the PKC␦ isoform, in dectin-1-mediated cytokine production (41). Our findings that MEK1/2 inhibition blocks the binding of Thr(P)-71-Thr-69 -ATF2 and the p38 MAPK inhibitor blunts both mRNA expression and Thr-69 -ATF2 binding, but not Thr(P)-71-ATF2 binding, can be explained by the complex mechanism of regulation of ATF2 activity, which was the first example of complementary phosphorylation of a single substrate by ERK and p38 MAPK.…”

Dectin-1-mediated Signaling Leads to Characteristic Gene Expressions and Cytokine Secretion via Spleen Tyrosine Kinase (Syk) in Rat Mast Cells

“…Cells-Fungal cell wall component ␤-glucan induces tyrosine phosphorylation of cellular proteins in macrophages (17) or in DCs (13). Therefore, first we analyzed whether curdlan could induce tyrosine phosphorylation of cellular proteins in mast cell line RBL-2H3 cells (Fig.…”

“…Upon ligand binding, hemITAM of Dectin-1 is phosphorylated by Src family protein-tyrosine kinases and recruits spleen tyrosine kinase (Syk) (10), which initiates a signaling cascade leading to nuclear factor-B (NF-B) (13,14), nuclear factor of activated T-cells (NFAT) (15,16), and MAPK activation (17)(18)(19). Traditional ITAM sequences, such as those found in Fc receptors, consist of a tandem repeat of YXX(I/L) sequences (where X is any amino acid), which, upon ligand binding and receptor clustering, become tyrosine-phosphorylated by Src kinases.…”

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…1), which activates MAPK (mitogen-activated protein kinase). [45][46][47] Dectin-1 signals are associated with Syk directly, while Dectin-2 and Mincle couple Syk via the common g-chain of Fc receptor. [48][49][50] Of note, in the Syk signaling pathway, CARD9 plays a crucial role to induce cytokine induction.…”