CD95 triggers Orai1-mediated localized Ca2+ entry, regulates recruitment of protein kinase C (PKC) β2, and prevents death-inducing signaling complex formation.

Abstract : The death receptor CD95 plays a pivotal role in immune surveillance and immune tolerance. Binding of CD95L to CD95 leads to recruitment of the adaptor protein Fas-associated death domain protein (FADD), which in turn aggregates caspase-8 and caspase-10. Efficient formation of the CD95/FADD/caspase complex, known as the death-inducing signaling complex (DISC), culminates in the induction of apoptosis. We show that cells exposed to CD95L undergo a reorganization of the plasma membrane in which the Ca(2+) release-activated Ca(2+) channel Orai1 and the endoplasmic reticulum-resident activator stromal interaction molecule 1 colocalize with CD95 into a micrometer-sized cluster in which the channel elicits a polarized entry of calcium. Orai1 knockdown and expression of a dominant negative construct (Orai1E106A) reveal that on CD95 engagement, the Orai1-driven localized Ca(2+) influx is fundamental to recruiting the Ca(2+)-dependent protein kinase C (PKC) β2 to the DISC. PKCβ2 in turn transiently holds the complex in an inactive status, preventing caspase activation and transmission of the apoptotic signal. This study identifies a biological role of Ca(2+) and the Orai1 channel that drives a transient negative feedback loop, introducing a lag phase in the early steps of the CD95 signal. We suggest that these localized events provide a time of decision to prevent accidental cell death.
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Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2011, 108 (47), pp.19072-7. 〈10.1073/pnas.1116946108〉
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Contributeur : Hervé De Villemeur <>
Soumis le : mardi 15 novembre 2011 - 12:01:20
Dernière modification le : mercredi 16 mai 2018 - 11:23:31

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Nadine Khadra, Laurence Bresson-Bepoldin, Aubin Penna, Benjamin Chaigne-Delalande, Bruno Ségui, et al.. CD95 triggers Orai1-mediated localized Ca2+ entry, regulates recruitment of protein kinase C (PKC) β2, and prevents death-inducing signaling complex formation.. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2011, 108 (47), pp.19072-7. 〈10.1073/pnas.1116946108〉. 〈inserm-00641268〉

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