Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1

Pose-Utrilla, Julia; García-Guerra, Lucía; Puerto, Ana del; Martín, Abraham; Jurado‐Arjona, Jerónimo; León-Reyes, Noelia S. de; Gamir-Morralla, Andrea; Sebastián-Serrano, Álvaro; Garcı́a-Gallo, Mónica; Kremer, Leonor; Fielitz, Jens; Ireson, Christofer; Pérez-Álvarez, MÂa José; Ferrer, Isidro; Hernández, Félix; Ávila, Jesús; Lasa, Marina; Campanero, Miguel R.; Iglesias, Teresa

doi:10.1038/s41467-017-02322-5

Cited by 25 publications

(22 citation statements)

References 61 publications

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“…This constitutive activity is beneficial for neuronal survival, as well as for learning and memory, and, thus, might favor the transcription of genes involved in these processes. However, NF-κB activation favored cell death or damage in pathophysiological models that involve NMDA receptor overactivation 56,57,58 while it resulted neuroprotective in cortical neurons both in vitro and in vivo 21 . It is unknown how an excitotoxic insult might switch NF-B activity to promote the expression of deleterious or pro-inflammatory proteins 59 .…”

Section: Nf-κb and Enos-dependent No Production In The Cerebral Cortexmentioning

confidence: 99%

eNOS-dependent S-nitrosylation of the NF-κB subunit p65 has neuroprotective effects

Caviedes

Maturana

Corvalán

et al. 2020

Preprint

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Cell death by glutamate excitotoxicity, mediated by N-methyl-D-aspartate (NMDA) receptors, negatively impacts brain function affecting hippocampal, i.e. sensitive neurons. The NF-κB transcription factor (composed mainly of p65/p50 subunits) contributes to neuronal death in excitotoxicity, while its inhibition should improve cell survival. Using the biotin switch method, subcellular fractionation, immunofluorescence and luciferase reporter assays, we found that NMDA stimulated NF-κB activity selectively in hippocampal neurons, while endothelial nitric oxide (eNOS), an enzyme expressed in neurons, is involved in the S-nitrosylation of p65 and consequent NF-κB inhibition in cerebrocortical, i.e. resistant neurons. The S-nitro proteomes of cortical and hippocampal neurons revealed that different biological processes are regulated by S-nitrosylation in susceptible and resistant neurons, bringing to light that protein S-nitrosylation is a ubiquitous posttranslational modification, able to influence a variety of biological processes including the homeostatic inhibition of the NF-κB transcriptional activity in cortical neurons exposed to excitotoxicity. Introduction.Neuronal death by glutamate excitotoxicity is implicated in the pathogenesis of several neurological disorders, ranging from neurodegeneration to epilepsy, stroke and traumatic brain injury (37, 52). The overstimulation of glutamate receptors leads to massive calcium influx, mainly through N-methyl-D-aspartate receptors (NMDA-Rs), triggering several intracellular pro-death signaling pathways (54). Endogenous/homeostatic protective mechanisms in response to glutamate, are incompletely known. In that line, the nuclear factor kappa B (NF-κB) family of transcription factors has been implicated in excitotoxicity in the retina, the striatum, cerebral cortex and hippocampus (29,44,53). This is associated with induction of pro-apoptotic and pro-inflammatory genes, including IL-1β. The canonic activation of the ubiquitous transcription factor NF-κB depends on phosphorylation and degradation of IκB proteins, leading to release and nuclear translocation of NF-κB, a dimer composed most frequently by a p65 and a p50 subunit (10,22). Its transcriptional activity in the nucleus is regulated by several post-translational modifications, such as phosphorylation and S-nitrosylation (i.e. the reversible coupling of nitric oxide (NO) to cysteine residues). In particular, S-nitrosylation of the p65 cysteine 38 inhibits its transcriptional activity in diverse cell types (24,41,46). However, the contribution of this mechanism to excitotoxicity is unknown and might imply a homeostatic regulation of the NF-κB activity. The main source of NO in the brain are nitric oxide synthases, i.e. the neuronal (nNOS), endothelial (eNOS) and inducible (iNOS) enzymes (5,9,15). Considering the novel finding that eNOS is present in neuronal cultures and in glutamatergic synapses (6), we examined whether eNOS is involved in p65 S-nitrosylation and thus, in the regulation of its transcriptional activit...

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Section: Nf-κb and Enos-dependent No Production In The Cerebral Cortexmentioning

confidence: 99%

eNOS-dependent S-nitrosylation of the NF-κB subunit p65 has neuroprotective effects

Caviedes

Maturana

Corvalán

et al. 2020

Preprint

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“…While PKD-induced NF- κ B activity in transformed cells contributes to tumor development, this pathway has recently also been shown to contribute to the physiological steady-state survival of neuronal cells. Indeed, in these cells, the PKD-NF- κ B-SOD2 axis is constitutively active and protects against oxidative damage [ 88 ]. In a model of excitotoxic neurodegeneration, which results in endoplasmic reticulum stress and mitochondrial dysfunction, high levels of ROS, and oxidative stress damage, the authors showed that PKD1 is rapidly deactivated after a short burst of activity, resulting in the loss of NF- κ B signaling and impeding neuronal survival [ 88 ].…”

Section: Protein Kinase Dmentioning

confidence: 99%

“…Indeed, in these cells, the PKD-NF- κ B-SOD2 axis is constitutively active and protects against oxidative damage [ 88 ]. In a model of excitotoxic neurodegeneration, which results in endoplasmic reticulum stress and mitochondrial dysfunction, high levels of ROS, and oxidative stress damage, the authors showed that PKD1 is rapidly deactivated after a short burst of activity, resulting in the loss of NF- κ B signaling and impeding neuronal survival [ 88 ]. These findings were further substantiated in vivo using patient samples and an ischemic mouse model [ 88 ].…”

Section: Protein Kinase Dmentioning

confidence: 99%

“…In a model of excitotoxic neurodegeneration, which results in endoplasmic reticulum stress and mitochondrial dysfunction, high levels of ROS, and oxidative stress damage, the authors showed that PKD1 is rapidly deactivated after a short burst of activity, resulting in the loss of NF- κ B signaling and impeding neuronal survival [ 88 ]. These findings were further substantiated in vivo using patient samples and an ischemic mouse model [ 88 ]. Another recent study in hippocampal primary neurons showed that PKD1 is transiently activated during oxidative stress, but no changes in NF- κ B signaling were observed by the authors [ 83 ].…”

Section: Protein Kinase Dmentioning

confidence: 99%

“…For example, as mentioned before, in neuronal cells, PKD1 activation does not always involve Tyr phosphorylation, but rather Ser-910 phosphorylation, and it does not contribute to an increased NF- κ B signaling output in these cells [ 83 , 84 ]. Moreover, a recent study shows a loss of homeostatic NF- κ B signaling output during increased oxidative stress due to a rapid downregulation of PKD1 activity [ 88 ].…”

Section: Concluding Remarks and Perspectivesmentioning

confidence: 99%

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Function and Regulation of Protein Kinase D in Oxidative Stress: A Tale of Isoforms

Cobbaut

Lint

2018

Oxidative Medicine and Cellular Longevity

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Oxidative stress is a condition that arises when cells are faced with levels of reactive oxygen species (ROS) that destabilize the homeostatic redox balance. High levels of ROS can cause damage to macromolecules including DNA, lipids, and proteins, eventually resulting in cell death. Moderate levels of ROS however serve as signaling molecules that can drive and potentiate several cellular phenotypes. Increased levels of ROS are associated with a number of diseases including neurological disorders and cancer. In cancer, increased ROS levels can contribute to cancer cell survival and proliferation via the activation of several signaling pathways. One of the downstream effectors of increased ROS is the protein kinase D (PKD) family of kinases. In this review, we will discuss the regulation and function of this family of ROS-activated kinases and describe their unique isoform-specific features, in terms of both kinase regulation and signaling output.

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Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1

Cited by 25 publications

References 61 publications

eNOS-dependent S-nitrosylation of the NF-κB subunit p65 has neuroprotective effects

eNOS-dependent S-nitrosylation of the NF-κB subunit p65 has neuroprotective effects

Function and Regulation of Protein Kinase D in Oxidative Stress: A Tale of Isoforms

SLC12A5 promotes hepatocellular carcinoma growth and ferroptosis resistance by inducing ER stress and cystine transport changes

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