Patched dependence receptor triggers apoptosis through ubiquitination of caspase-9.

Joanna Fombonne (1) , Pierre-Antoine Bissey (1) , Catherine Guix (1) , Rémy Sadoul (2) , Chantal Thibert (2) , Patrick Mehlen (1)

1 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
2 INSERM U836, équipe 2, Neurodégénérescence et plasticité

Patched (Ptc), the main receptor for Sonic Hedgehog, is a tumor suppressor. Ptc has been shown to be a dependence receptor, and as such triggers apoptosis in the absence of its ligand. This apoptosis induction occurs through the recruitment by the Ptc intracellular domain of a caspase-activating complex, which includes the adaptor proteins DRAL and TUCAN, and the apical caspase-9. We show here that this caspase-activating complex also includes the E3 ubiquitin ligase NEDD4. We demonstrate that Ptc-mediated apoptosis and Ptc-induced caspase-9 activation require NEDD4. We show that Ptc, but not Bax, the prototypical inducer of the intrinsic cell-death pathway, triggers polyubiquitination of caspase-9. Moreover, a caspase-9 mutant that could not be ubiquitinated failed to mediate Ptc-induced apoptosis. Taken together, these data support the view that the Ptc dependence receptor specifically allows the activation of caspase-9 via its ubiquitination, which occurs via the recruitment by Ptc of NEDD4.

Mots clés: posttranslational modification; protease; signalisation

Domaines: Biochimie, Biologie Moléculaire

Joanna Fombonne, Pierre-Antoine Bissey, Catherine Guix, Rémy Sadoul, Chantal Thibert, et al.. Patched dependence receptor triggers apoptosis through ubiquitination of caspase-9.. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109 (26), pp.10510-5. ⟨10.1073/pnas.1200094109⟩. ⟨inserm-00721053⟩