A pH- and ionic strength-dependent conformational change in the neck region regulates DNGR-1 function in dendritic cells

DNGR‐1 is receptor expressed by certain dendritic cell (DC) subsets and by DC precursors in mouse. It possesses a C‐type lectin‐like domain (CTLD) followed by a poorly characterized neck region coupled to a transmembrane region and short intracellular tail. The CTLD of DNGR‐1 binds F‐actin exposed by dead cell corpses and causes the receptor to signal and potentiate cross‐presentation of dead cell‐associated antigens by DCs. Here, we describe a conformational change that occurs in the neck region of DNGR‐1 in a pH‐ and ionic strength‐dependent manner and that controls cross‐presentation of dead cell‐associated antigens. We identify residues in the neck region that, when mutated, lock DNGR‐1 in one of the two conformational states to potentiate cross‐presentation. In contrast, we show that chimeric proteins in which the neck region of DNGR‐1 is replaced by that of unrelated C‐type lectin receptors fail to promote cross‐presentation. Our results suggest that the neck region of DNGR‐1 is an integral receptor component that senses receptor progression through the endocytic pathway and has evolved to maximize extraction of antigens from cell corpses, coupling DNGR‐1 function to its cellular localization. Synopsis The neck region of DNGR‐1, a dendritic cell receptor that mediates cross‐presentation of dead cell‐associated antigens, can undergo a pH‐ and ionic strength‐dependent conformational change. This allows internalized receptors to sense their relocalization from the cell surface to low pH endosomes and promotes endosomal extraction of antigens from engulfed cell corpses for cross‐presentation. The neck region of DNGR‐1 undergoes a conformational change in a pH‐ and ionic strength‐dependent manner. The conformational change happens predominantly at the level of tertiary structure. The integrity of the neck region is essential for the ability of DNGR‐1 to promote cross‐presentation. The conformational state impacts DNGR‐1 function. Graphical Abstract The dendritic cell receptor for dead cell‐associated antigens senses its relocalization from the cell surface through acidic endosomes to facilitate efficient cross‐presentation.