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| Content Provider | PubMed Central |
|---|---|
| Author | Jean-paul, Decuypere Kirsten, Welkenhuyzen Luyten, Tomas Ponsaerts, Raf Dewaele, Michael Jordi, Molgó Patrizia, Agostinis Missiaen, Ludwig De Smedt, Humbert Parys, Jan B. Bultynck, Geert |
| Copyright Year | 2011 |
| Abstract | The role of intracellular Ca2+ signaling in starvation-induced autophagy remains unclear. Here, we examined Ca2+ dynamics during starvation-induced autophagy and the underlying molecular mechanisms. Tightly correlating with autophagy stimulation, we observed a remodeling of the Ca2+ signalosome. First, short periods of starvation (1 to 3 h) caused a prominent increase of the ER Ca2+-store content and enhanced agonist-induced Ca2+ release. The mechanism involved the upregulation of intralumenal ER Ca2+-binding proteins, calreticulin and Grp78/BiP, which increased the ER Ca2+-buffering capacity and reduced the ER Ca2+ leak. Second, starvation led to Ins(1,4,5)P 3R sensitization. Immunoprecipitation experiments showed that during starvation Beclin 1, released from Bcl-2, first bound with increasing efficiency to Ins(1,4,5)P 3Rs; after reaching a maximal binding after 3 h, binding, however, decreased again. The interaction site of Beclin 1 was determined to be present in the N-terminal Ins(1,4,5)P 3-binding domain of the Ins(1,4,5)P 3R. The starvation-induced Ins(1,4,5)P 3R sensitization was abolished in cells treated with BECN1 siRNA, but not with ATG5 siRNA, pointing toward an essential role of Beclin 1 in this process. Moreover, recombinant Beclin 1 sensitized Ins(1,4,5)P 3Rs in 45Ca2+-flux assays, indicating a direct regulation of Ins(1,4,5)P 3R activity by Beclin 1. Finally, we found that Ins(1,4,5)P 3R-mediated Ca2+ signaling was critical for starvation-induced autophagy stimulation, since the Ca2+ chelator BAPTA-AM as well as the Ins(1,4,5)P 3R inhibitor xestospongin B abolished the increase in LC3 lipidation and GFP-LC3-puncta formation. Hence, our results indicate a tight and essential interrelation between intracellular Ca2+ signaling and autophagy stimulation as a proximal event in response to starvation. |
| Related Links | http://dx.doi.org/10.4161/auto.7.12.17909 |
| Ending Page | 1489 |
| Page Count | 18 |
| Starting Page | 1472 |
| File Format | |
| ISSN | 15548627 |
| e-ISSN | 15548635 |
| Journal | Autophagy |
| Issue Number | 12 |
| Volume Number | 7 |
| Language | English |
| Publisher | Landes Bioscience |
| Publisher Date | 2011-12-01 |
| Access Restriction | Open |
| Rights Holder | Landes Bioscience |
| Subject Keyword | Cell Biology Molecular Biology Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Molecular Biology |
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