IP 3 receptor-mediated Ca ( 2+) signaling and autophagy induction are interrelated. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Autophagy Année : 2011

IP 3 receptor-mediated Ca ( 2+) signaling and autophagy induction are interrelated.

Résumé

The role of intracellular Ca ( 2+) signaling in starvation-induced autophagy remains unclear. Here, we examined Ca ( 2+) dynamics during starvation-induced autophagy and the underlying molecular mechanisms. Tightly correlating with autophagy stimulation, we observed a remodeling of the Ca ( 2+) signalosome. Firstly, short periods of starvation (1 to 3 hr) caused a prominent increase of the ER Ca ( 2+) -store content and enhanced agonist-induced Ca ( 2+) release. The mechanism involved the upregulation of intraluminal ER Ca ( 2+) -binding proteins, calreticulin and Grp78/BiP, which increased the ER Ca2+-buffering capacity and reduced the ER Ca ( 2+) leak. Secondly, starvation led to IP 3R sensitization. Immunoprecipitation experiments showed that during starvation Beclin 1, released from Bcl-2, first bound with increasing efficiency to IP 3Rs; after reaching a maximal binding after 3 hr, binding however decreased again. The interaction site of Beclin 1 was determined to be present in the N-terminal IP 3-binding domain of the IP 3R. The starvation-induced IP 3R sensitization was abolished in cells treated with Beclin 1 siRNA, but not with Atg5 siRNA, pointing towards an essential role of Beclin 1 in this process. Moreover, recombinant Beclin 1 sensitized IP3Rs in ( 45) Ca ( 2+) -flux assays, indicating a direct regulation of IP3R activity by Beclin 1. Finally, we found that IP3R-mediated Ca ( 2+) signaling was critical for starvation-induced autophagy stimulation, since the Ca ( 2+) chelator BAPTA-AM as well as the IP 3R inhibitor Xestospongin B abolished the increase in LC3 lipidation and GFP-LC3-punctae formation. Hence, our results indicate a tight and essential interrelation between intracellular Ca ( 2+) signaling and autophagy stimulation as a proximal event in response to starvation.
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Dates et versions

hal-00683625 , version 1 (29-03-2012)

Identifiants

  • HAL Id : hal-00683625 , version 1
  • PUBMED : 22082873

Citer

Jean-Paul Decuypere, Kirsten Welkenhuyzen, Tomas Luyten, Raf Ponsaerts, Michael Dewaele, et al.. IP 3 receptor-mediated Ca ( 2+) signaling and autophagy induction are interrelated.. Autophagy, 2011, 7 (12), pp.1472-1489. ⟨hal-00683625⟩

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