NLRX1 dampens oxidative stress and apoptosis in tissue injury via control of mitochondrial activity

Stokman, Geurt; Kors, Lotte; Bakker, Pieter J.; Rampanelli, Elena; Claessen, Nike; Teske, Gwendoline J. D.; Butter, Loes M.; Andel, Harmen van; Weerman, Marius A. van den Bergh; Larsen, Per; Dessing, Mark C.; Zuurbier, Coert J.; Girardin, Stephen E.; Florquin, Sandrine; Leemans, Jaklien C.

doi:10.1084/jem.20161031

Cited by 91 publications

(83 citation statements)

References 40 publications

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“…Cells were seeded at a density of 20 000 cells/well on coverslips in 24‐well plates. After the indicated stimulation for 24‐72 hours, cells were washed in ice‐cold PBS, fixed in 4% paraformaldehyde in PBS and stained as described before . In short, cells were washed with PBS and incubated for 30 minutes in 0.1% Triton X‐100% and 0.5% BSA in PBS for blocking and permeabilization.…”

Section: Methodsmentioning

confidence: 99%

Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

Waasdorp

Rooij

Florquin

et al. 2018

J Cellular Molecular Medi

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End‐stage renal disease, the final stage of all chronic kidney disorders, is associated with renal fibrosis and inevitably leads to renal failure and death. Transition of tubular epithelial cells (TECs) into mesenchymal fibroblasts constitutes a proposed mechanism underlying the progression of renal fibrosis and here we assessed whether protease‐activated receptor (PAR)‐1, which recently emerged as an inducer of epithelial‐to‐mesenchymal transition (EMT), aggravates renal fibrosis. We show that PAR‐1 activation on TECs reduces the expression of epithelial markers and simultaneously induces mesenchymal marker expression reminiscent of EMT. We next show that kidney damage was reduced in PAR‐1‐deficient mice during unilateral ureter obstruction (UUO) and that PAR‐1‐deficient mice develop a diminished fibrotic response. Importantly, however, we did hardly observe any signs of mesenchymal transition in both wild‐type and PAR‐1‐deficient mice suggesting that diminished fibrosis in PAR‐1‐deficient mice is not due to reduced EMT. Instead, the accumulation of macrophages and fibroblasts was significantly reduced in PAR‐1‐deficient animals which were accompanied by diminished production of MCP‐1 and TGF‐β. Overall, we thus show that PAR‐1 drives EMT of TECs in vitro and aggravates UUO‐induced renal fibrosis although this is likely due to PAR‐1‐dependent pro‐fibrotic cytokine production rather than EMT.

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Section: Methodsmentioning

confidence: 99%

Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

Waasdorp

Rooij

Florquin

et al. 2018

J Cellular Molecular Medi

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“…NLRX1 is a pattern recognition receptor, but unlike other PRRs, it does not participate in the formation of inflammasomes, but rather it is localized in mitochondria. The studies on its function give contradictory results, while some investigators suggest that it induces production of the reactive oxygen species (ROS) [26], others demonstrate that NLRX1 dampens the oxidative stress [27]. NLRX1 is an important but poorly understood element of innate immunity.…”

Section: Treatment With a + N Or Cpt Upregulates Proteins Associated mentioning

confidence: 99%

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Krześniak

Zajkowicz

Gdowicz-Kłosok

et al. 2020

Cellular Signalling

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A B S T R A C TActinomycin D and nutlin-3a (A + N) activate p53, partly through induction of phosphorylation on Ser392. The death of A549 cells induced by A + N morphologically resembles inflammation-inducing pyroptosis -cell destruction triggered by activated caspase-1. The treatment with A + N (or camptothecin) strongly upregulated caspase-1 and its two activators: IFI16 and NLRP1, however, caspase-1 activation was not detected. A549 cells may have been primed for pyroptosis, with the absence of a crucial trigger. The investigation of additional innate immunity elements revealed that A + N (or camptothecin) stimulated the expression of NLRX1, STING (stimulator of interferon genes) and two antiviral proteins, IFIT1 and IFIT3. IFI16 and caspase-1 are coded by p53regulated genes which led us to investigate regulation of NLRP1, NLRX1, STING, IFIT1 and IFIT3 in p53-dependent mode. The upregulation of NLRP1, NLRX1 and STING was attenuated in p53 knockdown cells. The upsurge of the examined genes, and activation of p53, was inhibited by C16, an inhibitor of PKR kinase. PKR was tested due to its ability to phosphorylate p53 on Ser392. Surprisingly, C16 was active even in PKR knockdown cells. The ability of C16 to prevent activation of p53 and expression of innate immunity genes may be the source of its strong anti-inflammatory action. Moreover, cells exposed to A + N can influence neighboring cells in paracrine fashion, for instance, they shed ectodomain of COL17A1 protein and induce, in p53-dependent mode, the expression of gene for interleukin-7. Further, the activation of p53 also spurred the expression of SOCS1, an inhibitor of interferon triggered STAT1-dependent signaling. We conclude that, stimulation of p53 primes cells for the production of interferons (through upregulation of STING), and may activate negative-feedback within this signaling system by enhancing the production of SOCS1.

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“…The inhibitory antiviral activity of NLRX1 is not limited to MAVS, being also able to restrict NF‐κB activation by LPS and STING‐mediated type I IFN response activated by HIV‐1, herpes simplex virus‐1, and vaccinia virus . Interestingly, it has been recently shown that NLRX1 function is not limited to the regulation of antiviral pathways but also contributes to control mitochondrial activity preventing oxidative stress . Considering the functional similarities between LRPPRC and NLRX1, it will be interesting to assess whether the two proteins act synergistically in controlling antiviral responses or whether they are differentially activated depending on the type of pathogen‐associated molecular patterns.…”

Section: Discussionmentioning

confidence: 99%

“…GAPDH was analyzed as a loading control contributes to control mitochondrial activity preventing oxidative stress. (49) Considering the functional similarities between LRPPRC and NLRX1, it will be interesting to assess whether the two proteins act synergistically in controlling antiviral responses or whether they are differentially activated depending on the type of pathogen-associated molecular patterns.…”

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confidence: 99%

Negative Regulation of Mitochondrial Antiviral Signaling Protein–Mediated Antiviral Signaling by the Mitochondrial Protein LRPPRC During Hepatitis C Virus Infection

et al. 2018

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Hepatitis C virus (HCV) is highly efficient in establishing a chronic infection, having evolved multiple strategies to suppress the host antiviral responses. The HCV non-structural 5A (NS5A) protein, in addition to its role in viral replication and assembly, has long been known to hamper the interferon (IFN) response. However, the mechanism of this inhibitory activity of NS5A remains partly characterized. In a functional proteomic screening carried out in HCV replicon cells, we identified the mitochondrial protein LRPPRC as an NS5A binding factor. Notably, we found that downregulation of LRPPRC expression results in a significant inhibition of HCV infection, which is associated to an increased activation of the IFN response. Moreover, we showed that LRPPRC acts as a negative regulator of the mitochondrial-mediated antiviral immunity, by interacting with MAVS and inhibiting its association with TRAF3 and TRAF6. Finally, we demonstrated that NS5A is able to interfere with MAVS activity in a LRPPRC-dependent manner. Overall, our results indicate that NS5A contributes to the inhibition of innate immune pathways during HCV infection by exploiting the ability of LRPPRC to inhibit MAVS-regulated antiviral signaling. This article is protected by copyright. All rights reserved.

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NLRX1 dampens oxidative stress and apoptosis in tissue injury via control of mitochondrial activity

Abstract: NLRX1 is a mitochondrial innate immune receptor involved in viral immunity. Stokman et al. found that loss of NLRX1 increased cellular mitochondrial activity, production of reactive oxygen species, and apoptosis during oxidative stress in kidney injury.

Cited by 91 publications

References 40 publications

Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Negative Regulation of Mitochondrial Antiviral Signaling Protein–Mediated Antiviral Signaling by the Mitochondrial Protein LRPPRC During Hepatitis C Virus Infection

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