MARCH9‐mediated ubiquitination regulates MHC I export from the TGN

Given the heterogeneous nature of antigens, MHC-I intracellular transport intersects with multiple degradation pathways for efficient peptide loading and presentation to cytotoxic T cells. MHC-I loading with peptides in the endoplasmic reticulum (ER) is a tightly regulated process, while post-ER intracellular transport is considered to occur by default, leading to peptide-bearing MHC-I delivery to the plasma membrane. We show here that MHC-I traffic is submitted to a previously uncharacterized sorting step at the trans Golgi network (TGN), dependent on the ubiquitination of its cytoplasmic tail lysine residues. MHC-I ubiquitination is mediated by the E3 ligase MARCH9 and allows MHC-I access to syntaxin 6 (Stx6)-positive endosomal compartments. We further show that MARCH9 can also target the human MHC I-like lipid antigen presentation molecule CD1a. MARCH9 expression is modulated by microbial patterns exposure in dendritic cells (DC), thus revealing the role of this ubiquitin E3 ligase in coordinating MHC-I access to endosomes and DC activation for efficient antigen cross-presentation.