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 facilitates the processing of dead cell-derived antigen (Ag) for cross-presentation thereby controlling immune responses to infected and damaged cells. A major focus of our research is identification of the molecular mechanisms that underpin Clec9A function and the control of immune responses, 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 directly ubiquitinates the extracellular domains of Clec9A, to regulate receptor fate and antigen processing. At steady state, RNF41 ubiquitination of Clec9A facilitates novel interactions to regulate Clec9A levels. However, after dead cell uptake, these interactions are altered to favour antigen presentation. We define a non-canonical 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.