Cell surface dynamics and cellular distribution of endogenous FcRn

A major role for FcRn is the salvage of pinocytosed IgG and albumin from a degradative fate in lysosomes. FcRn achieves this by binding IgG in a pH-dependent manner in acidic endosomes and recycling it to the plasma membrane to be released at neutral pH. This is important in maintaining high serum IgG and albumin levels and has the potential to be exploited to modulate the pharmacokinetics of antibody-based therapeutics. Although FcRn is responsible for the recycling of IgG, the dynamic behaviour of endogenous FcRn is not well understood. Our data shows that the majority of endogenous receptor is distributed throughout the endosomal system and is present only at a low percentage on the plasma membrane at steady state. A significant fraction of FcRn at the cell surface appears to be endocytosis resistant while the remainder can undergo rapid endocytosis. To maintain surface levels of the receptor, endocytosed FcRn is replaced with FcRn from the internal pool. This unexpected complexity in FcRn cell surface dynamics has led us to propose a model for FcRn trafficking that should be taken into account when targeting FcRn at the cell surface for therapeutic purposes.