Disrupting the CD95-PLC gamma 1 interaction prevents Th17-driven inflammation

Amanda Poissonnier (1, 2) , Jean-Philippe Guegan (1, 2) , Ha Thanh Nguyen (2, 1) , Daniel Best (1, 2) , Nicolas Levoin (3) , Guennadi Kozlov (4) , Kalle Gehring (4) , Raphael Pineau (1, 2) , Florence Jouan (1, 2) , Lucie Morere (1, 2) , Sophie Martin (1, 2) , Melissa Thomas (1, 2) , Estibaliz Lazaro (5, 6) , Isabelle Douchet (5) , Thomas Ducret (7, 8) , Pierre van de Weghe (1, 2) , Patrick Blanco (5, 9) , Mickael Jean (1, 2) , Pierre Vacher (10) , Patrick Legembre (1, 2)

1 CRLCC - CRLCC Eugène Marquis
2 COSS - Chemistry, Oncogenesis, Stress and Signaling
3 Bioprojet-Biotech
4 McGill University = Université McGill [Montréal, Canada]
5 CIRID - Composantes innées de la réponse immunitaire et différenciation
6 Hôpital Haut-Lévêque [CHU Bordeaux]
7 UB - Université de Bordeaux
8 CRCTB - Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux]
9 CHU Bordeaux [Bordeaux]
10 ACTION - Actions for OnCogenesis understanding and Target Identification in ONcology

CD95L is a transmembrane ligand (m-CD95L) that is cleaved by metalloproteases to release a soluble ligand (s-CD95L). Unlike m-CD95L, interaction between s-CD95L and CD95 fails to recruit caspase-8 and FADD to trigger apoptosis and instead induces a Ca2+ response via docking of PLC gamma 1 to the calcium-inducing domain (CID) within CD95. This signaling pathway induces accumulation of inflammatory Th17 cells in damaged organs of lupus patients, thereby aggravating disease pathology. A large-scale screen revealed that the HIV protease inhibitor ritonavir is a potent disruptor of the CD95-PLC gamma 1 interaction. A structure-activity relationship approach highlighted that ritonavir is a peptidomimetic that shares structural characteristics with CID with respect to docking to PLC gamma 1. Thus, we synthesized CID peptidomimetics abrogating both the CD95-driven Ca2+ response and transmigration of Th17 cells. Injection of ritonavir and the CID peptidomimetic into lupus mice alleviated clinical symptoms, opening a new avenue for the generation of drugs for lupus patients.

Domains: Life Sciences [q-bio]; Cancer

Amanda Poissonnier, Jean-Philippe Guegan, Ha Thanh Nguyen, Daniel Best, Nicolas Levoin, et al.. Disrupting the CD95-PLC gamma 1 interaction prevents Th17-driven inflammation. Nature Chemical Biology, 2018, 14 (12), pp.1079-+. ⟨10.1038/s41589-018-0162-9⟩. ⟨hal-01976911⟩