Functions of RhoG in health and effects of RhoG deficiency.(A) Schematic depicting the normal stages of CD8⁺ T cell recognition and killing of target cells (Health). Upon activation, cytotoxic T lymphocytes (CTL) polarize and migrate toward the target cell via polymerization of actin (shown in red) at the leading edge of the cell, where RhoG (yellow) concentrates. CTLs then make contact with target cells, where they form a stable IS that is driven by the accumulation of actin and RhoG. Meanwhile, CGs (green) are transported to the IS. Granules dock at the IS in an area where actin has cleared through the direct interaction of RhoG with Munc13-4. Inset, The interaction of RhoG with Munc13-4 brings the CGs in contact with the plasma membrane (PM) of the CTL. Subsequent interaction of SNAP receptor (SNARE) proteins present in the CGs (Vamp8) and with those on the PM (Syntaxin 11, SNAP23), along with the SNARE-binding protein STXBP2, enables fusion of the CGs with the PM, releasing granule contents onto the target cell. (B) CTLs lacking expression of RhoG (RhoG deficiency) display reduced polarization and migration, abnormal IS morphology, reduced actin polymerization and clearance zones, and diminished CG exocytosis and target cell killing due to the inability of the granules to properly dock at the IS (inset).