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

Abstract : 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.
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01976911
Contributor : Laurent Jonchère <>
Submitted on : Thursday, January 10, 2019 - 1:35:02 PM
Last modification on : Thursday, June 18, 2020 - 12:32:06 PM

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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, Nature Publishing Group, 2018, 14 (12), pp.1079-+. ⟨10.1038/s41589-018-0162-9⟩. ⟨hal-01976911⟩

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