Peroxiredoxin-3 Is Involved in Bactericidal Activity through the Regulation of Mitochondrial Reactive Oxygen Species

Lee, Sena; Wi, Sae Mi; Min, Young Ki; Lee, Ki-Young

doi:10.4110/in.2016.16.6.373

Cited by 15 publications

(13 citation statements)

References 30 publications

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“…Western blotting and immunoprecipitation were performed as described previously (Kim et al, 2012, 2014; Yong Kim et al, 2013; Lee et al, 2016). Briefly, HEK293T cells were co-transfected with the designated vectors, as indicated in the Figures.…”

Section: Methodsmentioning

confidence: 99%

Peroxiredoxin-6 Negatively Regulates Bactericidal Activity and NF-κB Activity by Interrupting TRAF6-ECSIT Complex

Min

Shin

et al. 2017

Front. Cell. Infect. Microbiol.

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A TRAF6-ECSIT complex is crucial for the generation of mitochondrial reactive oxygen species (mROS) and nuclear factor-kappa B (NF-κB) activation induced by Toll-like receptor 4 (TLR4). Peroxiredoxin-6 (Prdx6) as a member of the peroxiredoxin family of antioxidant enzymes is involved in antioxidant protection and cell signaling. Here, we report on a regulatory role of Prdx6 in mROS production and NF-κB activation by TLR4. Prdx6 was translocated into the mitochondria by TLR4 stimulation and Prdx6-knockdown (Prdx6KD) THP-1 cells had increased level of mitochondrial reactive oxygen species levels and were resistant to Salmonella typhimurium infection. Biochemical studies revealed Prdx6 interaction with the C-terminal TRAF-C domain of TRAF6, which drove translocation into the mitochondria. Interestingly, Prdx6 competitively interacted with ECSIT to TRAF6 through its C-terminal TRAF-C domain, leading to the interruption of TRAF6-ECSIT interaction. The inhibitory effect was critically implicated in the activation of NF-κB induced by TLR4. Overexpression of Prdx6 led to the inhibition of NF-κB induced by TLR4, whereas Prdx6KD THP-1 cells displayed enhanced production of pro-inflammatory cytokines including interleukin-6 and -1β, and the up-regulation of NF-κB-dependent genes induced by TLR4 stimulation. Taken together, the data demonstrate that Prdx6 interrupts the formation of TRAF6-ECSIT complex induced by TLR4 stimulation, leading to suppression of bactericidal activity because of inhibited mROS production in mitochondria and the inhibition of NF-κB activation in the cytoplasm.

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Section: Methodsmentioning

confidence: 99%

Peroxiredoxin-6 Negatively Regulates Bactericidal Activity and NF-κB Activity by Interrupting TRAF6-ECSIT Complex

Min

Shin

et al. 2017

Front. Cell. Infect. Microbiol.

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“…Flow cytometric analysis of mROS production. mROS were detected within THP-1 cells as previously described (76). In brief, following treatments, cells were incubated with 2.5 μM MitoSOX (Invitrogen, Thermo Fisher Scientific; M36008) for 30 minutes, washed in PBS, removed from plates with ice-cold PBS supplemented with 1 mM EDTA, pelleted, and resuspended in ice-cold PBS supplemented with 1% FBS.…”

Section: Macrophage Ablation Experimentsmentioning

confidence: 99%

Blocking fatty acid–fueled mROS production within macrophages alleviates acute gouty inflammation

Hall¹,

Sanderson²,

Lawrence³

et al. 2018

Journal of Clinical Investigation

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Gout is the most common inflammatory arthritis affecting men. Acute gouty inflammation is triggered by monosodium urate (MSU) crystal deposition in and around joints that activates macrophages into a proinflammatory state, resulting in neutrophil recruitment. A complete understanding of how MSU crystals activate macrophages in vivo has been difficult because of limitations of live imaging this process in traditional animal models. By live imaging the macrophage and neutrophil response to MSU crystals within an intact host (larval zebrafish), we reveal that macrophage activation requires mitochondrial ROS (mROS) generated through fatty acid oxidation. This mitochondrial source of ROS contributes to NF-κB-driven production of IL-1β and TNF-α, which promote neutrophil recruitment. We demonstrate the therapeutic utility of this discovery by showing that this mechanism is conserved in human macrophages and, via pharmacologic blockade, that it contributes to neutrophil recruitment in a mouse model of acute gouty inflammation. To our knowledge, this study is the first to uncover an immunometabolic mechanism of macrophage activation that operates during acute gouty inflammation. Targeting this pathway holds promise in the management of gout and, potentially, other macrophage-driven diseases.

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“…Peroxiredoxins (Prdxs) are a family of proteins that function as antioxidants in cells [ 32 ]. It has been reported that Prdx3 is a mitochondrial protein that decreases mtROS levels [ 33 , 34 ]. In our MS detection data, the expression of Prdx3 was 6.5-fold greater in U937 cells than in the control after CKI treatment and was selected for further analysis due to its antioxidant activity.…”

Section: Resultsmentioning

confidence: 99%

“…Under oxidative stress conditions, PRDX3 is recruited to UNG1 binding to mtDNA and combines with UNG1 through a disulphide bond, protecting UNG1 from degradation and preventing oxidative damage to mitochondrial DNA to enhance the cell resistance to oxidative stress [ 40 ]. Studies have reported that the deletion of PRDX3 resulted in increased H 2 O 2 in the mitochondria [ 41 ], and the levels of mitochondrial ROS in THP-1 cells with the PRDX3 gene knocked out was significantly higher than in controls [ 33 ]. We have identified the increase in Prdx3 expression after CKI treatment by quantitative proteomics and have verified this increase in expression by qPCR, Western blot and immunohistochemistry.…”

Section: Discussionmentioning

confidence: 99%

Compound kushen injection suppresses human acute myeloid leukaemia by regulating the Prdxs/ROS/Trx1 signalling pathway

Jin

Yang

et al. 2018

J Exp Clin Cancer Res

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BackgroundThe increase in the levels of reactive oxygen species (ROS) in acute myeloid leukemia (AML) patients has been previously described; thus, it is important to regulate ROS levels in AML.MethodsFlow cytometry were used to assess the in vitro effect of compound kushen injection (CKI). Quantitative proteomics were used to analyse the mechanism. The AML patient-derived xenograft (PDX) model were used to evaluate the in vivo effect of CKI.ResultsWe found that intracellular ROS levels in AML cells were decreased, the antioxidant capacity were increased when treated with CKI. CKI inhibited the proliferation of AML cells and enhanced the cytotoxicity of AML cells, which has few toxic effects on haematopoietic stem cells (HSCs) and T cells. At the single-cell level, individual AML cells died gradually by CKI treatment on optofluidic chips. CKI promoted apoptosis and arrested cell cycle at G1/G0 phase in U937 cells. Furthermore, higher peroxiredoxin-3 (Prdx3) expression levels were identified in CKI-treated U937 cells through quantitative proteomics detection. Mechanically, the expression of Prdx3 and peroxiredoxin-2 (Prdx2) was up-regulated in CKI-treated AML cells, while thioredoxin 1 (Trx1) was reduced. Laser confocal microscopy showed that the proteins Prdx2 could be Interacted with Trx1 by CKI treatment. In vivo, the survival was longer and the disease was partially alleviated by decreased CD45+ immunophenotyping in peripheral blood in the CKI-treated group in the AML PDX model.ConclusionsAntioxidant CKI possess better clinical application against AML through the Prdxs/ROS/Trx1 signalling pathway.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0948-3) contains supplementary material, which is available to authorized users.

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Peroxiredoxin-3 Is Involved in Bactericidal Activity through the Regulation of Mitochondrial Reactive Oxygen Species

Cited by 15 publications

References 30 publications

Peroxiredoxin-6 Negatively Regulates Bactericidal Activity and NF-κB Activity by Interrupting TRAF6-ECSIT Complex

Peroxiredoxin-6 Negatively Regulates Bactericidal Activity and NF-κB Activity by Interrupting TRAF6-ECSIT Complex

Blocking fatty acid–fueled mROS production within macrophages alleviates acute gouty inflammation

Compound kushen injection suppresses human acute myeloid leukaemia by regulating the Prdxs/ROS/Trx1 signalling pathway

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