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The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells.

ABSTRACT: Ferroptosis is a recently discovered form of programmed cell death, but its regulatory mechanisms are not fully understood. In the current study, we reported that the BRD7-P53-SLC25A28 axis played a crucial role in regulating ferroptosis in hepatic stellate cells (HSCs). Upon exposure to ferroptosis inducers, bromodomain-containing protein 7 (BRD7) protein expression was remarkably increased through the inhibition of the ubiquitin-proteasome pathway. CRISPR/Cas9-mediated BRD7 knockout conferred resistance to HSC ferroptosis, whereas specific BRD7 plasmid-mediated BRD7 overexpression facilitated HSC ferroptosis. Interestingly, the elevated BRD7 expression exhibited to promote p53 mitochondrial translocation via direct binding with p53 N-terminal transactivation domain (TAD), which may be the underlying mechanisms for BRD7-enhanced HSC ferroptosis. Site-directed mutations of serine 392 completely blocked the binding of BRD7 to p53, and, in turn, prevented p53 mitochondrial translocation and HSC ferroptosis. Importantly, mitochondrial p53 interacted with solute carrier family 25 member 28 (SLC25A28) to form complex and enhanced the activity of SLC25A28, which could lead to the abnormal accumulation of redox-active iron and hyperfunction of electron transfer chain (ETC). SLC25A28 knockdown impaired BRD7-or p53-mediated ferroptotic events. In mice, erastin treatment ameliorated pathological damage of liver fibrosis through inducing HSC ferroptosis. HSC-specific blockade of BRD7-P53-SLC25A28 axis could abrogate erastin-induced HSC ferroptosis. Of note, we analyzed the effect of sorafenib on HSC ferroptosis in advanced fibrotic patients with hepatocellular carcinoma receiving sorafenib monotherapy. Attractively, BRD7 upregulation, p53 mitochondrial translocation, combination of SLC25A28 and p53, and ferroptosis induction occurred in primary human HSCs. Overall, these findings reveal novel signal transduction and regulatory mechanism of ferroptosis, and also suggest BRD7-P53-SLC25A28 axis as potential targets for liver fibrosis.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC7330619 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells.

Zhang Zili Z Guo Mei M Shen Min M Kong Desong D Zhang Feng F Shao Jiangjuan J Tan Shanzhong S Wang Shijun S Chen Anping A Cao Peng P Zheng Shizhong S

Redox biology 20200624

Ferroptosis is a recently discovered form of programmed cell death, but its regulatory mechanisms are not fully understood. In the current study, we reported that the BRD7-P53-SLC25A28 axis played a crucial role in regulating ferroptosis in hepatic stellate cells (HSCs). Upon exposure to ferroptosis inducers, bromodomain-containing protein 7 (BRD7) protein expression was remarkably increased through the inhibition of the ubiquitin-proteasome pathway. CRISPR/Cas9-mediated BRD7 knockout conferred ...[more]

PMID: 32863216

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Project description:Background & aimsInterleukin-15 (IL-15) and its high affinity receptor interleukin-15 receptor alpha (IL-15Rα) are widely expressed in immune cells and hepatic resident cells. IL-15 signaling has important functions in homeostasis of natural killer (NK), natural killer T (NKT) and cytotoxic T (CD8(+) T) cells, and in liver regeneration. We hypothesized that IL-15 has a protective role in liver fibrosis progression by maintaining NK cell homeostasis.MethodsFibrosis was induced using two mechanistically distinct models. Congenic bone marrow transplantation was used to evaluate the contribution of IL-15 signaling from various compartments to NK, CD8(+) T and NKT cell homeostasis and fibrogenesis. The gene expression profile of hepatic stellate cell (HSC) from IL-15Rα knockout (IL-15RαKO) mice and wild-type mice were captured using microarray analysis and validated in isolated HSC. Quantitative real-time PCR was used to assess repressors of collagen transcription.ResultsIL-15RαKO mice exhibited more fibrosis in both models. IL-15 signaling from specific types of hepatic cells had divergent roles in maintaining liver NK, CD8(+) T and NKT cells, with a direct and protective role on radio-resistant non-parenchymal cells beyond the control of NK homeostasis. HSCs isolated from IL-15RαKO mice demonstrated upregulation of collagen production. Finally, IL-15RαKO HSC with or without transforming growth factor beta (TGF-β) stimulation exhibited increased expression of fibrosis markers and decreased collagen transcription repressors expression.ConclusionsIL-15Rα signaling has a direct anti-fibrotic effect independent of preserving NK homeostasis. These findings establish a rationale to further explore the anti-fibrotic potential of enhancing IL-15 signaling in HSCs.Lay summaryWe investigated how a cellular protein, Interleukin-15 (IL-15), decreases the amount of scar tissue that is formed upon liver injury. We found that IL-15 and its receptor decrease the amount of scar tissue that is created by specialized liver cells (called stellate cells) and increase the number of a specific subgroup of immune cells (natural killer cells) that are known to eliminate stellate cells.Transcript profiling accession numberGSE45612, GSE 68001 and GSE 25097.

Project description:Ferroptosis is a recently discovered form of programmed cell death, but its regulatory mechanisms remain poorly understood. Here, we show that the RNA-binding protein ZFP36/TTP (ZFP36 ring finger protein) plays a crucial role in regulating ferroptosis in hepatic stellate cells (HSCs). Upon exposure to ferroptosis-inducing compounds, the ubiquitin ligase FBXW7/CDC4 (F-box and WD repeat domain containing 7) decreased ZFP36 protein expression by recognizing SFSGLPS motif. FBXW7 plasmid contributed to classical ferroptotic events, whereas ZFP36 plasmid impaired FBXW7 plasmid-induced HSC ferroptosis. Interestingly, ZFP36 plasmid inhibited macroautophagy/autophagy activation by destabilizing ATG16L1 (autophagy related 16 like 1) mRNA. ATG16L1 plasmid eliminated the inhibitory action of ZFP36 plasmid on ferroptosis, and FBXW7 plasmid enhanced the effect of ATG16L1 plasmid on autophagy. Importantly, ZFP36 plasmid promoted ATG16L1 mRNA decay via binding to the AU-rich elements (AREs) within the 3'-untranslated region. The internal mutation of the ARE region abrogated the ZFP36-mediated ATG16L1 mRNA instability, and prevented ZFP36 plasmid-mediated ferroptosis resistance. In mice, treatment with erastin and sorafenib alleviated murine liver fibrosis by inducing HSC ferroptosis. HSC-specific overexpression of Zfp36 impaired erastin- or sorafenib-induced HSC ferroptosis. Noteworthy, we analyzed the effect of sorafenib on HSC ferroptosis in fibrotic patients with hepatocellular carcinoma receiving sorafenib monotherapy. Attractively, sorafenib monotherapy led to ZFP36 downregulation, ferritinophagy activation, and ferroptosis induction in human HSCs. Overall, these results revealed novel molecular mechanisms and signaling pathways of ferroptosis, and also identified ZFP36-autophagy-dependent ferroptosis as a potential target for the treatment of liver fibrosis.AbbreviationsARE: AU-rich elements; ATG: autophagy related; BECN1: beclin 1; CHX: cycloheximide; COL1A1: collagen type I alpha 1 chain; ELAVL1/HuR: ELAV like RNA binding protein 1; FBXW7/CDC4: F-box and WD repeat domain containing 7; FN1: fibronectin 1; FTH1: ferritin heavy chain 1; GPX4/PHGPx: glutathione peroxidase 4; GSH: glutathione; HCC: hepatocellular carcinoma; HSC: hepatic stellate cell; LSEC: liver sinusoidal endothelial cell; MAP1LC3A: microtubule associated protein 1 light chain 3 alpha; MDA: malondialdehyde; NCOA4: nuclear receptor coactivator 4; PTGS2/COX2: prostaglandin-endoperoxide synthase 2; RBP: RNA-binding protein; ROS: reactive oxygen species; SLC7A11/xCT: solute carrier family 7 member 11; SQSTM1/p62: sequestosome 1; TNF: tumor necrosis factor; TP53/p53: tumor protein p53; UTR: untranslated region; ZFP36/TTP: ZFP36 ring finger protein.

Dataset Information

The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells.

Publications

The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells.

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