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

Torben Mentrup, Anna Yamina Stumpff-Niggemann, Nadja Leinung, Christine Schlosser, Katja Schubert, Rebekka Wehner, Antje Tunger, Valentin Schatz, Patrick Neubert, Ann-Christine Gradtke, Janina Wolf, Stefan Rose-John, Paul Saftig, Alexander Dalpke, Jonathan Jantsch, Marc Schmitz, Regina Fluhrer, Ilse D. Jacobsen and Bernd Schröder ()
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Torben Mentrup: Technische Universität Dresden
Anna Yamina Stumpff-Niggemann: Christian-Albrechts-University of Kiel
Nadja Leinung: Technische Universität Dresden
Christine Schlosser: Medical Faculty, University of Augsburg
Katja Schubert: Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute
Rebekka Wehner: Technische Universität Dresden
Antje Tunger: Technische Universität Dresden
Valentin Schatz: University Hospital of Regensburg and University of Regensburg
Patrick Neubert: University Hospital of Regensburg and University of Regensburg
Ann-Christine Gradtke: Technische Universität Dresden
Janina Wolf: Christian-Albrechts-University of Kiel
Stefan Rose-John: Christian-Albrechts-University of Kiel
Paul Saftig: Christian-Albrechts-University of Kiel
Alexander Dalpke: University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden
Jonathan Jantsch: University Hospital of Regensburg and University of Regensburg
Marc Schmitz: Technische Universität Dresden
Regina Fluhrer: Medical Faculty, University of Augsburg
Ilse D. Jacobsen: Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute
Bernd Schröder: Technische Universität Dresden

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29474-3

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