INAUGURAL ARTICLE by a Recently Elected Academy Member:MHC class II distribution in dendritic cells and B cells is determined by ubiquitin chain length

Dendritic cells (DCs) and B lymphocytes are professional antigen-presenting cells (APCs) capable of stimulating efficient T-cell responses (1, 2). However, their approaches to antigen presentation differ in important respects. Whereas DCs are highly endocytic and internalize a wide variety of antigens, B cells take up and process only the single antigen recognized by their B-cell receptor. DCs are also distinguished by their ability to regulate antigen processing and presentation by “maturation” (3, 4). Immature DCs, found in peripheral tissues, are adept at endocytic uptake of antigen but do not efficiently generate peptide–MHC class II (MHC II) complexes or express them stably on the cell surface. In part, this is because MHC II in immature DCs is ubiquitinated on a single conserved lysine in the cytoplasmic domain of the β-chain (5, 6) by E3 ligases of the membrane-associated RING-CH (MARCH) family (7, 8). Like other ubiquitinated membrane proteins (9), ubiquitinated MHC II molecules are targeted to and sequestered in multivesicular late endosomes and lysosomes. Upon receiving a maturation stimulus (e.g., Toll-like receptor agonist), however, ubiquitination ceases (5, 6) and peptide–MHC II complexes are translocated to and accumulate at the plasma membrane (10–13). In B cells, MHC II surface expression is always high despite also being ubiquitinated by MARCH ligases in naive B cells (8). Internalization and down-regulation of receptor tyrosine kinases by ubiquitination is well known. Ligand binding activates the kinase, resulting in autophosophorylation and subsequent recruitment of soluble E3 ligases (e.g., Cbl) that ubiquitinate one or more acceptor lysines. The ubiquitin (Ub) moieties are recognized by Ub-interaction motif (UIM)-containing adapter molecules (e.g., epsins, eps15) that associate with clathrin-coated pits, leading to receptor internalization (14–18). Upon delivery to early endosomes, Ub is recognized by members of the endosomal sorting complex required for transport (ESCRT) complexes 0–III, which prevent receptor recycling by facilitating entry of ubiquitinated cargo into nascent invaginations of the endosomal membrane (19). It is not known whether clathrin-coated pits and the ESCRT machinery recognize Ub similarly, or whether recognition requires a single Ub added to a single lysine, multiple lysines, or chains of Ub added to one or more sites (20–24). Nor is it known why ubiquitinated MHC II in naive B cells remains on the surface, whereas in immature DCs it is sequestered in late endocytic compartments. Here, we show that differences in MHC II trafficking between DCs and B cells are a consequence of differences in Ub chain length, not cell type.