Ins(1,4,5)P₃receptor-mediated Ca²⁺signaling and autophagy induction are interrelated

Abstract

Immunoprecipitation experiments showed that during starvation Beclin 1, released from Bcl-2, first bound with increasing efficiency to Ins(1,4,5)P 3 Rs; 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 3 R. The starvation-induced Ins(1,4,5)P 3 R 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 3 Rs in 45 Ca 2+ -flux assays, indicating a direct regulation of Ins(1,4,5)P 3 R activity by Beclin 1. Finally, we found that Ins(1,4,5) P 3 R-mediated Ca 2+ signaling was critical for starvation-induced autophagy stimulation, since the Ca 2+ chelator BAPTA-AM as well as the Ins(1,4,5)P 3 R 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 Ca 2+ signaling and autophagy stimulation as a proximal event in response to starvation.

Dysregulation of Endoplasmic Reticulum Stress and Autophagic Responses by the Antiretroviral Drug Efavirenz

“…In line with several studies demonstrating that alterations of calcium metabolism can induce autophagy (Decuypere et al, 2011(Decuypere et al, , 2013Ghislat et al, 2012), we also considered this mechanism in the present study. Although an increase in cytoplasmic calcium levels was observed in brain endothelial cells exposed to efavirenz, this increase did not result in stimulation of autophagy.…”

Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors

“…IP 3 R1 knockdown increases LC3-II (lapidated microtubule-associated protein light chain 3, LC3, an index of autophagy) content without changing the amount of actin (Fig. 3A), consistent with previous reports (24)(25)(26)(27). Furthermore, we found that TG2 knockdown had the opposite effect (Fig.…”

“…To examine the physiological role of this regulation in the cellular functions of IP 3 R1, we studied the role of TG2 and IP 3 R in autophagy. IP 3 R1 regulates autophagy (24)(25)(26)(27), and TG2 is also thought to regulate autophagy (50,51); however, the interplay between TG2 and IP 3 R1 in autophagy regulation has not been studied. We hypothesized that TG2 affects IP 3 R1-mediated autophagy regulation.…”

“…Dysregulation of IP 3 R1 is also implicated in neurodegenerative diseases including Huntington disease (HD) (16)(17)(18)) and Alzheimer's disease (AD) (19)(20)(21)(22). IP 3 Rs also control fundamental cellular processes-for example, mitochondrial energy production (23,24), autophagy regulation (24)(25)(26)(27), ER stress (28), hepatic gluconeogenesis (29), pancreatic exocytosis (30), and macrophage inflammasomes (31). On the other hand, excessive IP 3 R function promotes cell death processes including apoptosis by activating mitochondrial or calpain pathways (2,17).…”

Ca2+in quality control

“…25,65 Moreover, an additional study established that subjecting HeLa cells to short periods of starvation causes a prominent increase of the ER Ca 2+ -store content and enhances agonist-induced ER Ca 2+ release, resulting in autophagy. 66 A related study by Ghislat et al 67 found that starvation-induced autophagy proceeds via the CAMKK2-PRKAA-MTOR pathway.…”