Phosphorylation-driven effector switching of Rab7 and Rab12 by the leucine-rich repeat kinase 1 in mast cells

Here we show that activation by either IgE/antigen or the neuropeptide substance P, which binds to MRGPRX2, induces phosphorylation of the Rab GTPases Rab7 and Rab12. Phosphorylation of both GTPases was sensitive to protein kinase C (PKC) inhibition but resistant to inhibition of the leucine-rich repeat kinase 2 (LRRK2), a known Rab12 phosphorylating kinase. Furthermore, knockdown of the Leucine-Rich Repeat kinase 1 (LRRK1) suppressed phosphorylation of both Rab7 and Rab12, implicating LRRK1 in their phosphorylation by a PKC-dependent mechanism. Like phosphorylation by LRRK2, LRRK1-mediated phosphorylation of Rab12 increased its affinity for RILP-L1 and RILP-L2 while reducing binding to RILP. In contrast, LRRK1 phosphorylation of Rab7 enhanced its affinity for RILP.