Fig. 2. Regulation of CTLA-4 surface expression and internalization.

Newly synthesized CTLA-4 binds to the transmembrane adapter TRIM in the TGN promoting the formation of CTLA-4-containing vesicles and their transport to the cell surface. On the cell surface, CTLA-4 and TRIM no longer associate allowing TRIM to interact with other receptors, possibly the TCR complex. CTLA-4 externalization is also dependent on general factors such as PLD and GTPase ARF-1. Shuttling to the lysosomal compartment from the TGN occurs due to adapter AP-1 binding to GVY²⁰¹VKM motif in CTLA-4. On the surface, CTLA-4 becomes phosphorylated on the Y²⁰¹VKM by kinases Lck, Fyn, and Rlk leading to the association of PI3K and possibly other proteins. Phosphorylation retards internationalization. Dephosphorylation allows binding to the clathrin adapter AP-2 to the GVY²⁰¹VKM motif and rapid internalization to endosomes and lysosomes. Upon T-cell activation, CTLA-4 enriched lysosomes (and endosomes) are recycled to the cell surface. This process involves Wortmannin-sensitive lipid kinases but not PI3K (174). CTLA-4, cytotoxic T-lymphocyte antigen-4; TRIM, T-cell receptor-interacting molecule; TGN, trans-Golgi network; TCR, T-cell receptor; PLD, phospholipase D; ARF, adenosine diphosphate ribosylation factor; AP, adapter protein; PI3K, phosphatidylinositol 3-kinase.