Nuclear respiratory factor 1 promotes the progression of EBV-associated gastric cancer and maintains EBV latent infection

Yue, Liang; Li, Wen; Zhao, Menghe; Shi, Duo; Zhang, Yan; Luo, Bing

doi:10.1007/s11262-023-01970-8

Cited by 2 publications

(1 citation statement)

References 46 publications

(36 reference statements)

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“…Analysis of ChIP-Seq datasets shows that the ChIP-Seq identified NRF1 target genes in SK-N-SH cells are involved in various cellular processes such as mitochondrial function, RNA metabolism, DNA damage repair, cell cycle regulation, protein translation initiation, and ubiquitin-mediated protein degradation ( 42 ). Aberrant NRF1 has been linked to tumorigenesis, as some key oncogenes are regulated by NRF1, including genes related to glioblastoma ( 43 ), breast tumorigenesis ( 44 , 45 ), bladder cancer ( 46 ), prostate cancer ( 47 ), liver hepatocellular carcinoma ( 48 ) and EBV-associated gastric cancer ( 49 ). Therefore, in addition to being a crucial transcription factor, NRF1 has also emerged as a valuable biomarker for cancer diagnosis and prognosis.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanism of specific DNA sequence recognition by NRF1

Liu,

Li,

Xiao

et al. 2023

Nucleic Acids Research

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Nuclear respiratory factor 1 (NRF1) regulates the expression of genes that are vital for mitochondrial biogenesis, respiration, and various other cellular processes. While NRF1 has been reported to bind specifically to GC-rich promoters as a homodimer, the precise molecular mechanism governing its recognition of target gene promoters has remained elusive. To unravel the recognition mechanism, we have determined the crystal structure of the NRF1 homodimer bound to an ATGCGCATGCGCAT dsDNA. In this complex, NRF1 utilizes a flexible linker to connect its dimerization domain (DD) and DNA binding domain (DBD). This configuration allows one NRF1 monomer to adopt a U-turn conformation, facilitating the homodimer to specifically bind to the two TGCGC motifs in the GCGCATGCGC consensus sequence from opposite directions. Strikingly, while the NRF1 DBD alone could also bind to the half-site (TGCGC) DNA of the consensus sequence, the cooperativity between DD and DBD is essential for the binding of the intact GCGCATGCGC sequence and the transcriptional activity of NRF1. Taken together, our results elucidate the molecular mechanism by which NRF1 recognizes specific DNA sequences in the promoters to regulate gene expression.

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Section: Discussionmentioning

confidence: 99%

Molecular mechanism of specific DNA sequence recognition by NRF1

Liu,

Li,

Xiao

et al. 2023

Nucleic Acids Research

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Pterostilbene improves neurological dysfunction and neuroinflammation after ischaemic stroke via HDAC3/Nrf1-mediated microglial activation

Chen,

He,

Qiu

et al. 2024

Cell Mol Biol Lett

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Background Stroke is a type of acute brain damage that can lead to a series of serious public health challenges. Demonstrating the molecular mechanism of stroke-related neural cell degeneration could help identify a more efficient treatment for stroke patients. Further elucidation of factors that regulate microglia and nuclear factor (erythroid-derived 2)-like 1 (Nrf1) may lead to a promising strategy for treating neuroinflammation after ischaemic stroke. In this study, we investigated the possible role of pterostilbene (PTS) in Nrf1 regulation in cell and animal models of ischaemia stroke. Methods We administered PTS, ITSA1 (an HDAC activator) and RGFP966 (a selective HDAC3 inhibitor) in a mouse model of middle cerebral artery occlusion–reperfusion (MCAO/R) and a model of microglial oxygen‒glucose deprivation/reperfusion (OGD/R). The brain infarct size, neuroinflammation and microglial availability were also determined. Dual-luciferase reporter, Nrf1 protein stability and co-immunoprecipitation assays were conducted to analyse histone deacetylase 3 (HDAC3)/Nrf1-regulated Nrf1 in an OGD/R-induced microglial injury model. Results We found that PTS decreased HDAC3 expression and activity, increased Nrf1 acetylation in the cell nucleus and inhibited the interaction of Nrf1 with p65 and p65 accumulation, which reduced infarct volume and neuroinflammation (iNOS/Arg1, TNF-α and IL-1β levels) after ischaemic stroke. Furthermore, the CSF1R inhibitor PLX5622 induced elimination of microglia and attenuated the therapeutic effect of PTS following MCAO/R. In the OGD/R model, PTS relieved OGD/R-induced microglial injury and TNF-α and IL-1β release, which were dependent on Nrf1 acetylation through the upregulation of HDAC3/Nrf1 signalling in microglia. However, the K105R or/and K139R mutants of Nrf1 counteracted the impact of PTS in the OGD/R-induced microglial injury model, which indicates that PTS treatment might be a promising strategy for ischaemia stroke therapy. Conclusion The HDAC3/Nrf1 pathway regulates the stability and function of Nrf1 in microglial activation and neuroinflammation, which may depend on the acetylation of the lysine 105 and 139 residues in Nrf1. This mechanism was first identified as a potential regulatory mechanism of PTS-based neuroprotection in our research, which may provide new insight into further translational applications of natural products such as PTS.

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Nuclear respiratory factor 1 promotes the progression of EBV-associated gastric cancer and maintains EBV latent infection

Cited by 2 publications

References 46 publications

Molecular mechanism of specific DNA sequence recognition by NRF1

Molecular mechanism of specific DNA sequence recognition by NRF1

Pterostilbene improves neurological dysfunction and neuroinflammation after ischaemic stroke via HDAC3/Nrf1-mediated microglial activation

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