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dc.contributor.authorYoung, Christopher N. J.en
dc.contributor.authorSinadinos, Anthonyen
dc.contributor.authorLefebvre, Alexisen
dc.contributor.authorChan, Philippeen
dc.contributor.authorArkle, Stephenen
dc.contributor.authorVaudry, Daviden
dc.contributor.authorGorecki, Dariuszen
dc.date.accessioned2017-12-18T11:05:13Z
dc.date.available2017-12-18T11:05:13Z
dc.date.issued2015-02-20
dc.identifier.citationYoung, C.N.J., Sinadinos, A., Lefebvre, A., Chan, P., Arkle, D., Vaudry, D., Gorecki, D. (2015) A novel mechanism of autophagic cell death in dystrophic muscles via P2RX7 receptor large pore formation and Hsp90. Autophagy. 11 (1), pp. 113-130en
dc.identifier.urihttp://hdl.handle.net/2086/15014
dc.descriptionopen access articleen
dc.description.abstractP2RX7 is an ATP-gated ion channel, which can also exhibit an open state with a considerably wider permeation. However, the functional significance of the movement of molecules through the large pore (LP) and the intracellular signaling events involved are not known. Here, analyzing the consequences of P2RX7 activation in primary myoblasts and myotubes from the Dmd(mdx) mouse model of Duchenne muscular dystrophy, we found ATP-induced P2RX7-dependent autophagic flux, leading to CASP3-CASP7-independent cell death. P2RX7-evoked autophagy was triggered by LP formation but not Ca(2+) influx or MAPK1-MAPK3 phosphorylation, 2 canonical P2RX7-evoked signals. Phosphoproteomics, protein expression inference and signaling pathway prediction analysis of P2RX7 signaling mediators pointed to HSPA2 and HSP90 proteins. Indeed, specific HSP90 inhibitors prevented LP formation, LC3-II accumulation, and cell death in myoblasts and myotubes but not in macrophages. Pharmacological blockade or genetic ablation of p2rx7 also proved protective against ATP-induced death of muscle cells, as did inhibition of autophagy with 3-MA. The functional significance of the P2RX7 LP is one of the great unknowns of purinergic signaling. Our data demonstrate a novel outcome--autophagy--and show that molecules entering through the LP can be targeted to phagophores. Moreover, we show that in muscles but not in macrophages, autophagy is needed for the formation of this LP. Given that P2RX7-dependent LP and HSP90 are critically interacting in the ATP-evoked autophagic death of dystrophic muscles, treatments targeting this axis could be of therapeutic benefit in this debilitating and incurable form of muscular dystrophy.en
dc.language.isoenen
dc.publisherTaylor and Francisen
dc.titleA novel mechanism of autophagic cell death in dystrophic muscle regulated by P2RX7 receptor large-pore formation and HSP90.en
dc.typeArticleen
dc.identifier.doihttps://doi.org/10.4161/15548627.2014.994402
dc.peerreviewedYesen
dc.funderThis work was supported by the Interreg IV (TC2N) grant to DV and DCG, Duchenne Parents Project (NL) to DCG and Muscular Dystrophy Association USA to CY and DCG.en
dc.projectidSpring 2014en
dc.cclicenceCC-BY-NCen
dc.date.acceptance2015-02-01en
dc.researchinstituteLeicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)en


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