Peroxiredoxin 1 interacts with and blocks the redox factor APE1 from activating interleukin-8 expression

Abstract

APE1 is an essential DNA repair protein that also possesses the ability to regulate transcription. It has a unique cysteine residue C65, which maintains the reduce state of several transcriptional activators such as NF-κB. How APE1 is being recruited to execute the various biological functions remains unknown. Herein, we show that APE1 interacts with a novel partner PRDX1, a peroxidase that can also prevent oxidative damage to proteins by serving as a chaperone. PRDX1 knockdown did not interfere with APE1 expression level or its DNA repair activities. However, PRDX1 knockdown greatly facilitates APE1 detection within the nucleus by indirect immunofluorescence analysis, even though APE1 level was unchanged. The loss of APE1 interaction with PRDX1 promotes APE1 redox function to activate binding of the transcription factor NF-κB onto the promoter of a target gene, the proinflammatory chemokine IL-8 involved in cancer invasion and metastasis, resulting in its upregulation. Depletion of APE1 blocked the upregulation of IL-8 in the PRDX1 knockdown cells. Our findings suggest that the interaction of PRDX1 with APE1 represents a novel anti-inflammatory function of PRDX1, whereby the association safeguards APE1 from reducing transcription factors and activating superfluous gene expression, which otherwise could trigger cancer invasion and metastasis.

Targeting Peroxiredoxin 1 by a Curcumin Analogue, AI-44, Inhibits NLRP3 Inflammasome Activation and Attenuates Lipopolysaccharide-Induced Sepsis in Mice

“…It is worth pointing out that the function of PRDX1 is not restricted to its antioxidant activity. PRDX1 serves as a molecular chaperon by interacting with APE1 to maintain its protein level and DNA repair activity (28). Moreover, oligomeric PRDX1 directly associates with transcription factor p53 (29), c-Myc (30), NF-kB (31), or androgen receptor (32) in nucleus.…”

Knockout Mouse Models for Peroxiredoxins

“…PRDX1 is a ubiquitously expressed nuclear and cytosolic peroxidase protein and is a member of the typical 2-Cys PRDX subfamily [7,13]. PRDX1 is involved in tumor suppression [15][16][17][18], inflammation [13,[19][20][21][22][23][24][25][26], apoptosis [19,27,28], atherosclerosis [13,21], and molecular chaperoning [29,30]. According to the mouse Ensembl database, the Prdx1 gene is located on mouse chromosome 4 and there are five alternative forms of Prdx1 protein-coding transcripts [31].…”

Diagnostic performance of peroxiredoxin 1 to determine time-of-onset of acute cerebral infarction

“…PRDX-1 and GST-π belong to the antioxidant enzymes involved in the neutralization of reactive oxygen species (ROS) resulting from oxidative stress101112. Their induction and activation at different stages of cerebral infarction and inflammation, mainly described for peroxiredoxins, explain the high serum levels observed in stroke patients by Dayon et al .…”