ReviewEndosomal trafficking of open Major Histocompatibility Class I conformers-Implications for presentation of endocytosed antigens

Major Histocompatibility Class I (MHC-I) molecules are present at the cell surface either as fully conformed trimolecular complexes composed of heavy chain, beta-2-microglobulin (β2m) and antigenic peptide or as various open forms, devoid of the peptide and/or β2m. While the role of fully conformed MHC-I is well studied, the physiological role of open conformers is neglected. We have shown that fully conformed MHC-I and open MHC-I conformers segregate at the PM and during endosomal trafficking resulting in the exclusion of open MHC-I from the early endosomal/juxtanuclear recycling route. As a result, open MHC-I conformers are internalized with a higher rate than fully conformed counterparts. Although the majority of internalized open MHC-I is directed into the acidic late endosomal (LE) compartments, only a fraction of them is degraded. Namely, a significant fraction of open MHC-I is present in a subset of LEs with the capacity of recycling and/or exocytosis. Therefore, it should be examined whether exogenous peptide loading may occur during traveling of MHC-I proteins through LE compartments, especially in a subset of less acidic LEs that detach from the core of perinuclear acidic LEs and migrate toward the cell periphery. Given that the acidic LE environment is not favorable for peptide loading, an endosomal compartment with the recycling capacity and less acidic environment that allows stabilization of newly formed trimolecular complexes is proper site for exogenous peptide loading. We propose that a LE compartment which collect and retain open MHC-I conformers should be taken into consideration as a site of exogenous peptide loading.

► Physiological role of open MHC-I conformers is neglected. ► Fully conformed MHC-I and open MHC-I conformers segregate at the plasma membrane and during endosomal trafficking. ► Open MHC-I conformers are excluded from the early endosomal recycling route. ► Majority of internalized open MHC-I conformers is directed into the acidic LEs with the capacity of recycling/exocytosis. ► LE compartment which collect and retain open MHC-I molecules should be considered as a site of exogenous peptide loading.