Tyrosine phosphatase SHP-2 mediates C-type lectin receptor–induced activation of the kinase Syk and anti-fungal TH17 responses

Abstract

SUMMARYFungal infection stimulates the canonical C-type lectin receptors (CLRs) signaling pathway via Syk activation. Here we show that SHP-2 plays a crucial role in mediating CLRs-induced Syk activation. Genetic ablation of Shp-2 (Ptpn11) in dendritic cells (DCs) and macrophages impaired Syk-mediated signaling and abrogated pro-inflammatory gene expression following fungal stimulation. Mechanistically, SHP-2 operates as a scaffold facilitating the recruitment of Syk to dectin-1 or FcRγ, through its N-SH2 domain and a previously unrecognized C-terminal ITAM motif. We demonstrate that DC-derived SHP-2 is crucial for the induction of IL-1β, IL-6 and IL-23, and anti-fungal TH17 cell responses to control Candida albicans infection. Together, these data reveal a mechanism by which SHP-2 mediates Syk activation in response to fungal infections

Immune Interactions with Pathogenic and Commensal Fungi: A Two-Way Street

“…A recent study provides a potential solution by demonstrating that the SHP-2 phosphatase promotes Dectin-1-mediated Syk phosphorylation (Figure 1; Deng et al, 2015). Although the phosphatase activity of SHP-2 has been well characterized, the study shows that SHP-2 has a cryptic ITAM site, which is important for optimal Dectin-1 phosphorylation and signaling.…”

“…Although the phosphatase activity of SHP-2 has been well characterized, the study shows that SHP-2 has a cryptic ITAM site, which is important for optimal Dectin-1 phosphorylation and signaling. SHP-2 is also required for controlling systemic candidiasis (Deng et al, 2015). …”

Immunity against fungi

“…β-Glucan binding displaces regulatory phosphatases CD45 and CD148 (25), induces SRC-dependent phosphorylation of the intracellular ITAM-like motif, and recruits the SHP-2 phosphatase (26). SYK docks to this scaffold and transduces signals via PKC-δ (27) and the VAV family of GEFs (28) to CARD9, which complexes with BCL10 and MALT1 (29) to activate the canonical NF-κB subunits p65 and c-REL (30).…”

The innate immune signaling in cancer and cardiometabolic diseases: Friends or foes?

“…Dectin-1 is one of the most important members of Syk-coupled CLRs with ITAM domains [33]. Binding of Dectin-1 to its ligand leads to the phosphorylation of the hemITAM motifs, thus inducing Syk recruitment [34].…”