A siRNA screen reveals the prosurvival effect of protein kinase A activation in conditions of unresolved endoplasmic reticulum stress

Aguileta, Miguel; Rojas‐Rivera, Diego; Goossens, Vera; Estornes, Yann; Isterdael, Gert Van; Vandenabeele, Peter; Bertrand, Mathieu J.M.

doi:10.1038/cdd.2016.59

Cited by 11 publications

(11 citation statements)

References 52 publications

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“…Next, we tested whether early ER stress-induced organelle remodelling depends on PKA signalling, as this kinase reportedly has pro-survival effects during stress [19, 23, 24]. As expected, we observed mitochondrial elongation in wild-type HeLa cells during early ER stress, as determined via three-dimensional (3D) reconstruction using confocal microscopy (Fig.…”

Section: Resultsmentioning

confidence: 62%

“…Of note, DRP1-mediated fragmentation occurs at the ER–mitochondria interface [20] and is regulated by ER-localized proteins [21, 22]. Similarly, ER stress also leads to PKA activation as a protective mechanism [23], which is partially due to DRP1 phosphorylation [24]. Interestingly, DRP1 phosphorylation at Ser637 upon ER stress has been associated with its translocation to the ER, where it participates in ER expansion triggered to cope with protein misfolding [25].…”

Section: Introductionmentioning

confidence: 99%

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Caveolin-1 impairs PKA-DRP1-mediated remodelling of ER–mitochondria communication during the early phase of ER stress

et al. 2018

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Close contacts between endoplasmic reticulum and mitochondria enable reciprocal Ca exchange, a key mechanism in the regulation of mitochondrial bioenergetics. During the early phase of endoplasmic reticulum stress, this inter-organellar communication increases as an adaptive mechanism to ensure cell survival. The signalling pathways governing this response, however, have not been characterized. Here we show that caveolin-1 localizes to the endoplasmic reticulum-mitochondria interface, where it impairs the remodelling of endoplasmic reticulum-mitochondria contacts, quenching Ca transfer and rendering mitochondrial bioenergetics unresponsive to endoplasmic reticulum stress. Protein kinase A, in contrast, promotes endoplasmic reticulum and mitochondria remodelling and communication during endoplasmic reticulum stress to promote organelle dynamics and Ca transfer as well as enhance mitochondrial bioenergetics during the adaptive response. Importantly, caveolin-1 expression reduces protein kinase A signalling, as evidenced by impaired phosphorylation and alterations in organelle distribution of the GTPase dynamin-related protein 1, thereby enhancing cell death in response to endoplasmic reticulum stress. In conclusion, caveolin-1 precludes stress-induced protein kinase A-dependent remodelling of endoplasmic reticulum-mitochondria communication.

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Section: Resultsmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Caveolin-1 impairs PKA-DRP1-mediated remodelling of ER–mitochondria communication during the early phase of ER stress

et al. 2018

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“…PKA protects cells from ER stress and Akap 1 regulates PKA ( Gewandter et al, 2009 ; Aguileta et al, 2016 ). The presence of PKA negatively regulates the JNK protein ( Zeitlin et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Protein Akap1 Deletion Exacerbates Endoplasmic Reticulum Stress in Mice Exposed to Hyperoxia

et al. 2022

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Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), are treated with high concentrations of supplementary oxygen. However, prolonged exposure to high oxygen concentrations stimulates the production of reactive oxygen species (ROS), which damages the mitochondria and accumulates misfolded proteins in the endoplasmic reticulum (ER). The mitochondrial protein A-kinase anchoring protein 1 (Akap1) is critical for mitochondrial homeostasis. It is known that Akap1 deficiency results in heart damage, neuronal development impairment, and mitochondrial malfunction in preclinical studies. Our laboratory recently revealed that deleting Akap1 increases the severity of hyperoxia-induced ALI in mice. To assess the role of Akap1 deletion in ER stress in lung injury, wild-type and Akap1−/− mice were exposed to hyperoxia for 48 h. This study indicates that Akap1−/− mice exposed to hyperoxia undergo ER stress, which is associated with an increased expression of BiP, JNK phosphorylation, eIF2α phosphorylation, ER stress-induced cell death, and autophagy. This work demonstrates that deleting Akap1 results in increased ER stress in the lungs of mice and that hyperoxia exacerbates ER stress-related consequences.

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“…The siRNA oligonucleotides had the following sequences: p-1, 5′-AGCTTCTGTCCGGATCTAA-3′ with the sequence 5′-ACGTAGATCCTTCAGCACC-3′ was designed as a negative control. siRNA-β-arrestin or siRNA-control were transfected into Klebsiella pneumoniae cells for further analysis according to the protocol of a previous study ( 29 ).…”

Section: Methodsmentioning

confidence: 99%

Antibiotic resistance of Klebsiellaï¿½pneumoniae through β-arrestin recruitment-induced β-lactamase signaling pathway

et al. 2018

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Overuse and misuse of antibiotics leads to rapid evolution of antibiotic-resistant bacteria and antibiotic resistance genes. Klebsiella pneumoniae has become the most common pathogenic bacterium accountable for nosocomial infections due to its high virulence factor and general occurrence of resistance to most antibiotics. The β-lactamase signaling pathway has been suggested to be involved in antibiotic resistance against β-lactams in Klebsiella pneumoniae. In the present study, the molecular mechanism of the antibiotic resistance of Klebsiella pneumoniae was investigated and the results indicated involvement of the β-arrestin recruitment-induced β-lactamase signaling pathway. Antimicrobial susceptibility of Klebsiella pneumoniae was assessed using automated systems and extended-spectrum β-lactamase (ESBL) and β-arrestin expression levels in Klebsiella pneumoniae were analyzed by reverse-transcription quantitative PCR. β-lactam resistance in Klebsiella pneumoniae was determined using β-lactam agar screening plates. The results demonstrated that β-arrestin recruitment was increased in Klebsiella pneumoniae with antibiotic resistance (AR-K.P.) compared with that in the native Klebsiella pneumoniae strain (NB-K.P.). Increased production of ESBL was observed in AR-K.P. after treatment with the β-lactam penicillin. Of note, inhibition of β-arrestin recruitment significantly suppressed ESBL expression in AR-K.P. and in addition, genes encoding β-arrestin and ESBL were upregulated in Klebsiella pneumoniae. Restoration of endogenous β-arrestin markedly increased antibiotic resistance of Klebsiella pneumoniae to β-lactam. Knockdown of endogenous β-arrestin downregulated antibiotic resistance genes and promoted the inhibitory effects of β-lactam antibiotic treatment on Klebsiella pneumoniae growth. In conclusion, the present study identified that β-arrestin recruitment was associated with growth and resistance to β-lactams, which suggested that β-arrestin regulating ESBL expression may be a potential target for addressing antibiotic resistance to β-lactams in Klebsiella pneumoniae.

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A siRNA screen reveals the prosurvival effect of protein kinase A activation in conditions of unresolved endoplasmic reticulum stress

Cited by 11 publications

References 52 publications

Caveolin-1 impairs PKA-DRP1-mediated remodelling of ER–mitochondria communication during the early phase of ER stress

Caveolin-1 impairs PKA-DRP1-mediated remodelling of ER–mitochondria communication during the early phase of ER stress

Mitochondrial Protein Akap1 Deletion Exacerbates Endoplasmic Reticulum Stress in Mice Exposed to Hyperoxia

Antibiotic resistance of Klebsiellaï¿½pneumoniae through β-arrestin recruitment-induced β-lactamase signaling pathway

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