A decrease in cellular energy status stimulates PERK-dependent eIF2α phosphorylation and regulates protein synthesis in pancreatic β-cells

Gomez, Edith; Powell, Mike; Bevington, Alan; Herbert, Terence P.

doi:10.1042/bj20071367

Cited by 57 publications

(62 citation statements)

References 46 publications

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“…Probably because of insufficient UPR, autophagy-deficient beta cells were found to be susceptible to ER stressors in vitro and in vivo, which is consistent with previous reports suggesting that UPR is not only a marker of, but also an adaptation to, ER stress, and that insufficient UPR in the presence of ER stress renders cells prone to cell death [20]. Our data from Atg7 Δβ-cell mice are different from previous studies showing increased UPR in autophagy-deficient tissue [27,28], which may be attributable to peculiarities of pancreatic beta cells with respect to ER stress [29]. In our experiment to elucidate the mechanism of compromised expression of UPR genes, we observed reduced production of p85α and p85β non-catalytic subunits of PI3K, which would lead to deficient accumulation of nuclear XBP-1 and reduced expression of UPR genes [18,19].…”

Section: Discussioncontrasting

confidence: 57%

Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice

et al. 2011

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Aims/hypothesis The unfolded protein response (UPR) in endoplasmic reticulum (ER) and autophagy are known to be related. We investigated the role of autophagy in UPR of pancreatic beta cells and the susceptibility of autophagydeficient beta cells to the ER stress that is implicated in the development of diabetes. Methods Rat insulin promoter (RIP)-Cre + ;autophagy-related 7 (Atg7) F/W mice were bred with ob/w mice to derive RIP-Cre + ;Atg7 F/F -ob/ob mice and to induce ER stress in vivo. GFP-LC3 + -ob/ob mice were generated to examine in vivo autophagic activity. Real-time RT-PCR was performed to study the expression of the genes of the UPR machinery. Proteolysis was assessed by determining release of incorporated radioactive leucine.Results Production of UPR machinery was reduced in autophagy-deficient beta cells, which was associated with diminished production of p85α and p85β regulatory subunits of phosphoinositide 3-kinase. Because of compromised UPR machinery, autophagy-deficient beta cells were susceptible to ER stressors in vitro. When mice with beta cell-specific autophagy deficiency, which have mild hyperglycaemia, were bred with ob/ob mice to induce ER stress in vivo, severe diabetes developed, which was accompanied by an increase in beta cell death and accumulation of reactive oxygen species. The increased demand for UPR present in obesity was unmet in autophagy-deficient beta cells. Autophagy level and autophagic activity were enhanced by lipid, while proteolysis was reduced. Conclusions/interpretation These results suggest that autophagy is important for intact UPR machinery and appropriate UPR in response to lipid injury that increases demand for UPR. Autophagy deficiency in pancreatic beta cells may contribute to the progression from obesity to diabetes.

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Section: Discussioncontrasting

confidence: 57%

Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice

et al. 2011

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“…In fact, the UPR was first identified as a response to glucose limitation, which leads to an accumulation of misfolded proteins by impairing protein glycosylation. Interestingly, activation of PERK, one of the key pathways of the UPR, is stimulated in some cases in response to glucose deprivation by pathways that are independent of misfolded protein accumulation (41). These precedents underscore the important functional link between energy homeostasis and the UPR, mediated through various yet unknown molecular mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Adenylate Kinase 2 Links Mitochondrial Energy Metabolism to the Induction of the Unfolded Protein Response

Burkart

Shi

Chouinard

et al. 2011

Journal of Biological Chemistry

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The unfolded protein response (UPR) is a homeostatic signaling mechanism that balances the protein folding capacity of the endoplasmic reticulum (ER) with the secretory protein load of the cell. ER protein folding capacity is dependent on the abundance of chaperones, which is increased in response to UPR signaling, and on a sufficient ATP supply for their activity. An essential branch of the UPR entails the splicing of XBP1 mRNA to form the XBP1 transcription factor. XBP1 has been shown to be required during adipocyte differentiation, enabling mature adipocytes to secrete adiponectin, and during differentiation of B cells into antibody-secreting plasma cells. Here we find that adenylate kinase 2 (AK2), a mitochondrial enzyme that regulates adenine nucleotide interconversion within the intermembrane space, is markedly induced during adipocyte and B cell differentiation. Depletion of AK2 by RNAi impairs adiponectin secretion in 3T3-L1 adipocytes, IgM secretion in BCL1 cells, and the induction of the UPR during differentiation of both cell types. These results reveal a new mechanism by which mitochondria support ER function and suggest that specific mitochondrial defects may give rise to impaired UPR signaling. The requirement for AK2 for UPR induction may explain the pathogenesis of the profound hematopoietic defects of reticular dysgenesis, a disease associated with mutations of the AK2 gene in humans.Cellular homeostasis depends on the continuous synthesis of transmembrane and secretory proteins to maintain cellular integrity and an appropriate extracellular environment. These proteins are translocated into the endoplasmic reticulum (ER) 2 for post-translational processing, involving the function of numerous chaperones that catalyze ATP-dependent protein folding. When the need for endoplasmic reticulum folding capacity rises (ER stress), a transient inhibition of protein synthesis is triggered followed by an increase in chaperone levels. This coordinated response is known as the unfolded protein response (UPR). When the UPR fails to resolve ER stress, a global response is triggered that can lead to apoptosis and is linked to multiple human pathologies (1-5).The UPR is initiated through three known signaling pathways, the PERK, ATF6, and IRE1 pathways (2, 6, 7). PERK activation transiently decreases protein synthesis, and ATF6 is proteolytically cleaved to form a transcription factor that induces chaperone transcription. IRE1 is a bifunctional kinase/site-specific endoribonuclease that catalyzes XBP1 mRNA splicing, generating a stable mRNA product (sXBP1) from which the transcription factor XBP1 is translated. Like ATF6, XBP1 induces chaperone transcription. An important feature of IRE1 is that, unlike other autophosphorylating kinases, IRE1 is not activated by self-phosphorylation but rather by the occupancy of its ATP binding site (8).Given the requirement for ATP in chaperone function and IRE1 activation, the initiation and maintenance of the UPR are likely to be influenced by cellular energy levels. Several o...

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“…14) and/or metabolic pathways. The UPR during hypoxia resembles the beta cell response to low non-stimulatory glucose concentrations where ATP and ER [Ca 2+ ] levels and protein synthesis are reduced [43,[48][49][50]. However, the inhibitory effect of hypoxia on the adaptive UPR is observed even in the presence of low glucose concentrations (not shown) suggesting additional mechanisms.…”

Section: Hypoxia Impairs Er-to-golgi Protein Trafficking In Beta Cellsmentioning

confidence: 92%

Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells

et al. 2016

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Aims/hypothesis Hypoxia may contribute to beta cell failure in type 2 diabetes and islet transplantation. The adaptive unfolded protein response (UPR) is required for endoplasmic reticulum (ER) homeostasis. Here we investigated whether or not hypoxia regulates the UPR in beta cells and the role the adaptive UPR plays during hypoxic stress. Methods Mouse islets and MIN6 cells were exposed to various oxygen (O 2 ) tensions. DNA-damage inducible transcript 3 (DDIT3), hypoxia-inducible transcription factor (HIF)1α and HSPA5 were knocked down using small interfering (si)RNA; Hspa5 was also overexpressed. db/db mice were used. Results Hypoxia-response genes were upregulated in vivo in the islets of diabetic, but not prediabetic, db/db mice. In isolated mouse islets and MIN6 cells, O 2 deprivation (1-5% vs 20%; 4-24 h) markedly reduced the expression of adaptive UPR genes, including Hspa5, Hsp90b1, Fkbp11 and spliced Xbp1. Coatomer protein complex genes (Copa, Cope, Copg [also known as Copg1], Copz1 and Copz2) and ER-to-Golgi protein trafficking were also reduced, whereas apoptotic genes (Ddit3, Atf3 and Trb3 [also known as Trib3]), c-Jun N-terminal kinase (JNK) phosphorylation and cell death were increased. Inhibition of JNK, but not HIF1α, restored adaptive UPR gene expression and ER-to-Golgi protein trafficking while protecting against apoptotic genes and cell death following hypoxia. DDIT3 knockdown delayed the loss of the adaptive UPR and partially protected against hypoxia-induced cell death. The latter response was prevented by HSPA5 knockdown. Finally, Hspa5 overexpression significantly protected against hypoxia-induced cell death. Conclusions/interpretation Hypoxia inhibits the adaptive UPR in beta cells via JNK and DDIT3 activation, but independently of HIF1α. Downregulation of the adaptive UPR contributes to reduced ER-to-Golgi protein trafficking and increased beta cell death during hypoxic stress.

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A decrease in cellular energy status stimulates PERK-dependent eIF2α phosphorylation and regulates protein synthesis in pancreatic β-cells

Cited by 57 publications

References 46 publications

Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice

Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice

Adenylate Kinase 2 Links Mitochondrial Energy Metabolism to the Induction of the Unfolded Protein Response

Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells

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