Modulation of FcγRI (CD64) ligand binding by blocking peptides of periplakin

FcγRI requires both the intracellular domain of the α-chain and associated leukocyte Fc receptor (FcR) γ-chains for its biological function. We recently found the C terminus of periplakin to selectively interact with the cytoplasmic domain of the FcγRI α-chain. It thereby enhances the capacity of FcγRI to bind, internalize, and present antigens on MHC class II. Here, we characterized the domains involved in FcγRI-periplakin interaction using truncated and alanine-substituted FcγRI mutants and randomly mutagenized periplakin. This allowed us to design TAT peptides that selectively interfered with endogenous FcγRI-periplakin interactions. The addition of these peptides to FcγRI-expressing cells modulated FcγRI ligand binding, as assessed by erythrocyte-antibody-rosetting. These data support a dominant-negative role of C-terminal periplakin for FcγRI biological activity and implicate periplakin as a novel regulator of FcγRI in immune cells.