Phagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis

TLDR

Pattern recognition receptors, such as Dectin‑1, detect fungal β‑glucans to initiate host defence, yet their activation must be tightly controlled to prevent tissue damage. We demonstrate that Dectin‑1a is cleaved to a stable phagosomal fragment that signals until removed by SPPL2a/b, and that SPPL2b‑deficient cells show enhanced ROS, killing, and cytokine responses, highlighting intramembrane proteases as regulators of anti‑fungal immunity.

Abstract

Sensing of pathogens by pattern recognition receptors (PRR) is critical to initiate protective host defence reactions. However, activation of the immune system has to be carefully titrated to avoid tissue damage necessitating mechanisms to control and terminate PRR signalling. Dectin-1 is a PRR for fungal β-glucans on immune cells that is rapidly internalised after ligand-binding. Here, we demonstrate that pathogen recognition by the Dectin-1a isoform results in the formation of a stable receptor fragment devoid of the ligand binding domain. This fragment persists in phagosomal membranes and contributes to signal transduction which is terminated by the intramembrane proteases Signal Peptide Peptidase-like (SPPL) 2a and 2b. Consequently, immune cells lacking SPPL2b demonstrate increased anti-fungal ROS production, killing capacity and cytokine responses. The identified mechanism allows to uncouple the PRR signalling response from delivery of the pathogen to degradative compartments and identifies intramembrane proteases as part of a regulatory circuit to control anti-fungal immune responses.