DOCK8 Regulates Macrophage Migration through Cdc42 Activation and LRAP35a Interaction [Immunology]

DOCK8 is an atypical guanine nucleotide exchange factor (GEF) for Cdc42, and its mutations cause combined immunodeficiency in humans. Accumulating evidence indicates that DOCK8 regulates the migration and activation of various subsets of leukocytes, yet its regulatory mechanism is poorly understood. We herein report that DOCK8-deficient macrophages exhibit a migration defect in a two-dimensional (2D) setting. Although DOCK8 deficiency in macrophages did not affect the global Cdc42 activation induced by chemokine stimulation, rescue experiments revealed that the GEF activity of DOCK8 was required for macrophage migration. We found that DOCK8 associated with LRAP35a, an adaptor molecule that binds to the Cdc42 effector MRCK, and facilitated its activity to phosphorylate myosin-II regulatory light chain. When this interaction was disrupted in WT macrophages, they showed a migration defect, as seen in DOCK8-deficient macrophages. These results suggest that during macrophage migration, DOCK8 links Cdc42 activation to actomyosin dynamics through the association with LRAP35a.

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