Role of Inositol Trisphosphate Receptors in Autophagy in DT40 Cells

Khan, Muhammad Tariq Masood; Joseph, Suresh K.

doi:10.1074/jbc.m110.114207

Cited by 86 publications

(100 citation statements)

References 62 publications

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“…Consistent with many other studies, MTOR activation was unaltered. Conversely, the study by Khan et al 76 detected no change in PRKAA activation, but demonstrated a decrease in MTOR activity. Specifically, the downregulation of the SRC-related kinase FYN in lymphocytes by dexamethasone, a glucocorticoid used widely as both a chemotherapeutic and immunosuppressive agent, leads to reduced phosphorylation of ITPR and decreased Ca 2+ release, but also a reduction in MTOR activity.…”

Section: + As An Autophagy Suppressormentioning

confidence: 81%

“…Overexpression of another major ER Ca 2+ channel, RYR, does not have the same effect, and expression of a channelinactive mutant of ITPR in TKO cells is similarly unable to restore wild-type autophagic activity, highlighting not only the significance of ITPRs but the release of Ca 2+ in the regulation of autophagy. 75,76 These two studies do conflict, however, with regard to downstream mechanisms. Cárdenas et al 75 suggested a mechanism by which abolished ITPR Ca 2+ release leads to an increased AMP/ATP ratio, PRKAA activation and consequent stimulation of autophagy.…”

Section: + As An Autophagy Suppressormentioning

confidence: 87%

“…Studies 75,76 In these cells the levels of autophagy are higher than in wild-type controls, and ectopic overexpression of ITPRs in TKO cells restores autophagy to wild-type levels. Overexpression of another major ER Ca 2+ channel, RYR, does not have the same effect, and expression of a channelinactive mutant of ITPR in TKO cells is similarly unable to restore wild-type autophagic activity, highlighting not only the significance of ITPRs but the release of Ca 2+ in the regulation of autophagy.…”

Section: + As An Autophagy Suppressormentioning

confidence: 99%

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Campanella

2013

Autophagy

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Section: + As An Autophagy Suppressormentioning

confidence: 81%

Section: + As An Autophagy Suppressormentioning

confidence: 87%

Section: + As An Autophagy Suppressormentioning

confidence: 99%

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Campanella

2013

Autophagy

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“…Knockdown of IP 3 R impairs the activity of mTORC1 but not the Beclin 1 core complex in chicken DT40 B-lymphocyte cells. 62 PINK1. PTEN-induced putative kinase 1 (PINK1) is a serine/ threonine protein kinase that localizes to mitochondria.…”

Section: Slammentioning

confidence: 99%

The Beclin 1 network regulates autophagy and apoptosis

et al. 2011

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Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP 3 R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes, thereby inducing autophagy. In contrast, the BH3 domain of Beclin 1 is bound to, and inhibited by Bcl-2 or Bcl-XL. This interaction can be disrupted by phosphorylation of Bcl-2 and Beclin 1, or ubiquitination of Beclin 1. Interestingly, caspase-mediated cleavage of Beclin 1 promotes crosstalk between apoptosis and autophagy. Beclin 1 dysfunction has been implicated in many disorders, including cancer and neurodegeneration. Here, we summarize new findings regarding the organization and function of the Beclin 1 network in cellular homeostasis, focusing on the cross-regulation between apoptosis and autophagy. Cell Death and Differentiation (2011) 18, 571-580; doi:10.1038/cdd.2010 published online 11 February 2011 Autophagy is an essential process that consists of selective degradation of cellular components. There are at least three different types of autophagy described and possibly more. These autophagy types include macroautophagy (hereafter referred to as autophagy), microautophagy and chaperonemediated autophagy. 1 The initial step of autophagy is the surrounding and sequestering of cytoplasmic organelles and proteins within an isolation membrane (phagophore). Potential sources for the membrane to generate the phagophore include the Golgi complex, endosomes, the endoplasmic reticulum (ER), mitochondria and the plasma membrane. 2 The nascent membranes are fused at their edges to form double-membrane vesicles, called autophagosomes. Autophagosomes undergo a stepwise maturation process, including fusion with acidified endosomal and/or lysosomal vesicles, eventually leading to the delivery of cytoplasmic contents to lysosomal components, where they fuse, then degrade and are recycled (Figure 1a). The process of mammalian autophagy is divided into six principal steps: initiation (Figure 1b It has been well demonstrated that autophagy depends on Atg5/Atg7, is associated with microtubule-associated protein light chain 3 (LC3) truncation and lipidation, and may originate directly from the ER membrane and other membrane organelles. Furthermore, recent study has identified a Atg5/Atg7-independent pathway of autophagy. 3 This pathway of autophagy was not associated with LC3 processing but appeared to involve autophagosome formation from late endosomes and the trans-Golgi. 3 Atg7-independent autophagy had been implicated in mitochondrial clearance from reticulocytes. 4 The exact molecular basis of Atg5/Atg7-independent autophagy remains to be elucidated. Interestingly, Beclin 1 is required for Atg5/Atg7-dependent and -independent autophagy. 3 However, the presence of Beclin 1-indep...

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“…22 Recently, it has been shown that knockdown or chemical inhibition of Ins(1,4,5) P 3 Rs, or depletion of Ins(1,4,5)P 3 induce autophagy. [23][24][25] In this respect, Ins(1,4,5)P 3 Rs seem to be essential for a constitutive Ca 2+ release from the ER to mitochondria to support mitochondrial bioenergetics. 26 As a result, depletion or inhibition of Ins(1,4,5) P 3 Rs will result in a decline in the Ca 2+ -dependent production of ATP, an increase in the AMP/ATP ratio and subsequent activation of the AMP-activated protein kinase (AMPK), leading to stimulation of autophagy.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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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.

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Role of Inositol Trisphosphate Receptors in Autophagy in DT40 Cells

Cited by 86 publications

References 62 publications

Ca²⁺in quality control

Ca²⁺in quality control

The Beclin 1 network regulates autophagy and apoptosis

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

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Role of Inositol Trisphosphate Receptors in Autophagy in DT40 Cells

Cited by 86 publications

References 62 publications

Ca2+in quality control

Ca2+in quality control

The Beclin 1 network regulates autophagy and apoptosis

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

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Ca²⁺in quality control

Ca²⁺in quality control

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