Dendritic cells (DC) use a variety of cell surface receptors to monitor the environment for potential dangers, including cells that have died of non-homeostatic causes (eg. infected cells), to induce appropriate immune responses. Clec9A is a DC-specific Damage-Associated Molecular Pattern receptor, that recognises actin filaments exposed on dead cells, and facilitates the processing of dead cell-derived antigen (Ag) for cross-presentation and the induction of effective immune responses. A major focus of our research is identification of the molecular mechanisms that underpin Clec9A function and the control of immune responses to dead cell-associated Ag, and on the development of Clec9A-targeting approaches for enhancing immune responses.
We recently identified a novel regulator of Clec9A and Ag cross-presentation, the E3 Ubiquitin ligase RNF41. We discovered RNF41 ubiquitinates Clec9A to regulate its downstream fate. Intriguingly, RNF41 regulates Clec9A by ubiquitination of the Clec9A extracellular domains, revealing a novel mechanism of receptor regulation. We thus define a new ubiquitination-mediated mechanism for the regulation of Clec9A, reflecting the unique properties of Clec9A as a receptor specialized for delivery of antigens for cross-presentation. These findings provide important insights into antigen cross-presentation and have implications for the development of approaches to modulate immune responses.