Neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting ERAD activation

Pintado, Cristina; Macias, Sandra; Dominguez-Martín, Helena; Castaño, Angélica; Ruano, Diego

doi:10.1038/s41598-017-08722-3

Cited by 25 publications

(23 citation statements)

References 40 publications

(58 reference statements)

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“…Hence, it is not surprising that recent research has brought the role of UPR in neuroinflammation into focus as a converging pathological pathway. Indeed, recent work has highlighted the existence of a one-directional cause-and-effect relationship between activation of the UPR due to proteasome dysfunction and neurodegeneration (83)(84)(85). Here, our results support a role for the UPR in triggering neuroinflammation, which is a key component of neurodegenerative diseases.…”

Section: Discussionsupporting

confidence: 84%

Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

et al. 2019

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Proteostasis is critical for cells to maintain the balance between protein synthesis, quality control, and degradation. This is particularly important for myeloid cells of the central nervous system as their immunological function relies on proper intracellular protein turnover by the ubiquitin-proteasome system. Accordingly, disruption of proteasome activity due to, e.g., loss-of-function mutations within genes encoding proteasome subunits, results in systemic autoinflammation. On the molecular level, pharmacological inhibition of proteasome results in endoplasmic reticulum (ER) stress-activated unfolded protein response (UPR) as well as an induction of type I interferons (IFN). Nevertheless, our understanding as to whether and to which extent UPR signaling regulates type I IFN response is limited. To address this issue, we have tested the effects of proteasome dysfunction upon treatment with proteasome inhibitors in primary murine microglia and microglia-like cell line BV-2. Our data show that proteasome impairment by bortezomib is a stimulus that activates all three intracellular ER-stress transducers activation transcription factor 6, protein kinase R-like endoplasmic reticulum kinase and inositol-requiring protein 1 alpha (IRE1α), causing a full activation of the UPR. We further demonstrate that impaired proteasome activity in microglia cells triggers an induction of IFNβ1 in an IRE1-dependent manner. An inhibition of the IRE1 endoribonuclease activity significantly attenuates TANK-binding kinase 1-mediated activation of type I IFN. Moreover, interfering with TANK-binding kinase 1 activity also compromised the expression of C/EBP homologous protein 10, thereby emphasizing a multilayered interplay between UPR and type IFN response pathway. Interestingly, the induced protein kinase R-like endoplasmic reticulum kinase-activation transcription factor 4-C/EBP homologous protein 10 and IRE1-X-box-binding protein 1 axes caused a significant upregulation of proinflammatory cytokine interleukin 6 expression that exacerbates STAT1/STAT3 signaling in cells with dysfunctional proteasomes. Altogether, these findings indicate that proteasome impairment disrupts ER homeostasis and triggers a complex interchange between ER-stress sensors and type I IFN signaling, thus inducing in myeloid cells a state of chronic inflammation.

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Section: Discussionsupporting

confidence: 84%

Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

et al. 2019

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“…2a). Proteasomal function can be compromised by the neuroinflammation which often accompanies neurodegeneration [32, 41–44], and as Sho has a nucleic acid–binding region [29] suggestive of a role in molecular pattern recognition after infections, we also tested the effects of two innate immune ligands. Although glycosylated Sho levels were mildly decreased by these treatments ( p = 0.0295 for poly I:C), unlike the effect of proteasomal inhibitors, we were unable to detect a commensurate increase in level for the unglycosylated forms of Sho (Fig.…”

Section: Resultsmentioning

confidence: 99%

Proteasomal Inhibition Redirects the PrP-Like Shadoo Protein to the Nucleus

et al. 2019

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The Shadoo protein (Sho) exhibits homology to the hydrophobic region of the cellular isoform of prion protein (PrPC). As prion-infected brains gradually accumulate infectivity-associated isoforms of prion protein (PrPSc), levels of mature endogenous Sho become reduced. To study the regulatory effect of the proteostatic network on Sho expression, we investigated the action of lactacystin, MG132, NH4Cl, and 3-methyladenine (3-MA) in two cell culture models. In primary mixed neuronal and glial cell cultures (MNGCs) from transgenic mice expressing wild-type Sho from the PrP gene promoter (Tg.Sprn mice), lactacystin- and MG132-mediated inhibition of proteasomal activity shifted the repertoire of Sho species towards unglycosylated forms appearing in the nuclei; conversely, the autophagic modulators NH4Cl and 3-MA did not affect Sho or PrPC glycosylation patterns. Mouse N2a neuroblastoma cells expressing Sho under control of a housekeeping gene promoter treated with MG132 or lactacystin also showed increased nuclear localization of unglycosylated Sho. As two proteasomal inhibitors tested in two cell paradigms caused redirection of Sho to nuclei at the expense of processing through the secretory pathway, our findings define a balanced shift in subcellular localization that thereby differs from the decreases in net Sho species seen in prion-infected brains. Our data are indicative of a physiological pathway to access Sho functions in the nucleus under conditions of impaired proteasomal activity. We also infer that these conditions would comprise a context wherein Sho’s N-terminal nucleic acid–binding RGG repeat region is brought into play.Electronic supplementary materialThe online version of this article (10.1007/s12035-019-1623-1) contains supplementary material, which is available to authorized users.

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“…These lines of evidence highlight a possibility that autophagy serves as the common machinery in regulating microglia-mediated inflammation in response to a multitude of inflammatory stimuli. Yet, another study demonstrated that LPS injection induced autophagy activation in rat hippocampus ( Pintado et al, 2017 ). Autophagy is a catabolic process that can be activated during starvation, stress and nutrient deprivation by different signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

A Critical Role of Autophagy in Regulating Microglia Polarization in Neurodegeneration

Jin

Wang

et al. 2018

Front. Aging Neurosci.

137

106

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Neuroinflammation and autophagy dysfunction are closely related to the development of neurodegeneration such as Parkinson’s disease (PD). However, the role of autophagy in microglia polarization and neuroinflammation is poorly understood. TNF-α, which is highly toxic to dopaminergic neurons, is implicated as a major mediator of neuroinflammation in PD. In this study, we found that TNF-α resulted in an impairment of autophagic flux in microglia. Concomitantly, an increase of M1 marker (iNOS/NO, IL-1β, and IL-6) expression and reduction of M2 marker (Arginase1, Ym1/2, and IL-10) were observed in TNF-α challenged microglia. Upregulation of autophagy via serum deprivation or pharmacologic activators (rapamycin and resveratrol) promoted microglia polarization toward M2 phenotype, as evidenced by suppressed M1 and elevated M2 gene expression, while inhibition of autophagy with 3-MA or Atg5 siRNA consistently aggravated the M1 polarization induced by TNF-α. Moreover, Atg5 knockdown alone was sufficient to trigger microglia activation toward M1 status. More important, TNF-α stimulated microglia conditioned medium caused neurotoxicity when added to neuronal cells. The neurotoxicity was further aggravated when Atg5 knockdown in BV2 cells but alleviated when microglia pretreatment with rapamycin. Activation of AKT/mTOR signaling may contribute to the changes of autophagy and inflammation as the AKT specific inhibitor perifosine prevented the increase of LC3II (an autophagic marker) in TNF-α stimulated microglia. Taking together, our results demonstrate that TNF-α inhibits autophagy in microglia through AKT/mTOR signaling pathway, and autophagy enhancement can promote microglia polarization toward M2 phenotype and inflammation resolution.

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Neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting ERAD activation

Cited by 25 publications

References 40 publications

Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

Proteasomal Inhibition Redirects the PrP-Like Shadoo Protein to the Nucleus

A Critical Role of Autophagy in Regulating Microglia Polarization in Neurodegeneration

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