Abstract
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.
Highlights
Recognition of damage-associated molecular patterns (DAMPs), molecules released or exposed by cells upon injury, is essential for maintenance of homeostasis and tissue repair (Zelenay & Reis e Sousa, 2013)
By non-reducing SDS–PAGE followed by Western blotting for FLAG, all extracellular domains (ECDs) ran as dimers, with a minor fraction in the form of higher order oligomers (Fig 1A)
DNGR-1 is a sensor of extracellular form of actin (F-actin) that allows dendritic cell (DC) to detect the presence of cell debris (Sancho et al, 2009)
Summary
Recognition of damage-associated molecular patterns (DAMPs), molecules released or exposed by cells upon injury, is essential for maintenance of homeostasis and tissue repair (Zelenay & Reis e Sousa, 2013). It can lead to adaptive immune responses against proteins present within dead cells, including cancer neoantigens (Zelenay & Reis e Sousa, 2013). DNGR-1 ( known as CLEC9A) is a vertebrate DAMP receptor expressed by certain types of dendritic cells (DCs), leukocytes that couple innate and adaptive immunity. DNGR-1 can act as an endocytic receptor, yet it is dispensable for uptake of dead cell debris by DCs (Huysamen et al, 2008; Sancho et al, 2008, 2009). DNGR-1 recognition of F-actin favors the cross-presentation of dead cell-associated antigens by DCs that internalized dead cell debris (Sancho et al, 2009; Iborra et al, 2012; Zelenay et al, 2012). The exact mechanism by which DNGR-1 exerts this function remains elusive but is thought to involve regulation of the maturation of endosomes containing dead cell material (Sancho et al, 2009; Iborra et al, 2012; Zelenay et al, 2012)
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