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Disrupting the CD95-PLCγ1 interaction prevents Th17-driven inflammation.

A new interesting article has been published in Nat Chem Biol. 2018 Dec;14(12):1079-1089. doi: 10.1038/s41589-018-0162-9. Epub 2018 Nov 14. and titled:

Disrupting the CD95-PLCγ1 interaction prevents Th17-driven inflammation.

Authors of this article are:

Poissonnier A, Guégan JP, Nguyen HT, Best D, Levoin N, Kozlov G, Gehring K, Pineau R, Jouan F, Morere L, Martin S, Thomas M, Lazaro E, Douchet I, Ducret T, van de Weghe P, Blanco P, Jean M, Vacher P,0, Legembre P.

A summary of the article is shown below:

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 PLCγ1 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-PLCγ1 interaction. A structure-activity relationship approach highlighted that ritonavir is a peptidomimetic that shares structural characteristics with CID with respect to docking to PLCγ1. 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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