Syk activation during FcγR-mediated phagocytosis involves Syk palmitoylation and desulfenylation.

The Syk tyrosine kinase acts downstream of several immune receptors such as the FcγR. Syk owns two SH2 domains that interact with biphosphorylated ITAMs of the FcγR upon phagocytosis. This results in the activation of Syk by autophosphorylation, triggering phosphorylation of several downstream targets, F-actin polymerization, and phagocytosis of the IgG-opsonized target. We found that Syk is S-acylated upon phagocytosis by macrophages. Palmitoylation is performed on a single Syk-Cys by the DHHC5 enzyme that specifically associates with Syk upon phagocytosis. Syk palmitoylation is important for Syk localization to the phagocytic cup, phosphorylation, and phagocytosis. We observed that another Syk-Cys residue, within a redox motif, is modified by sulfenylation. Nevertheless, Syk desulfenylation seems to occur during phagocytosis, when H(2)O(2) production at the cup decreases, after 3.5 min of phagocytosis. Molecular dynamics studies indicated that desulfenylation increased the exposure of a loop within the Syk interdomain B. This could facilitate phosphorylation of key Syk-Tyr residues by upstream kinases. We thus propose an updated model for Syk activation during FcγR-mediated phagocytosis that involves both Syk palmitoylation and desulfenylation.