S-nitrosylation of EMMPRIN Influences the Migration of HSCs and MMP Activity in Liver Fibrosis

Overview

Journal Acta Biochim Biophys Sin (Shanghai)

Specialties Biochemistry
Biophysics

Date 2023 Sep 13

PMID 37700592

Authors

Xinyan Zhu

Zihui Tang

Wei Li

Xiaojuan Li

Yasuko Iwakiri

Fei Liu

Affiliations

Soon will be listed here.

Abstract

The mechanism of extracellular matrix metalloproteinase inducer (EMMPRIN) in the regulation of liver fibrosis has not been clarified. This study aims to investigate the role of EMMPRIN S-nitrosylation (SNO) in the regulation of hepatic stellate cell (HSC) migration and matrix metalloproteinase (MMP) activities in liver fibrosis. The results from the tissue microarrays and rat/mouse liver tissues suggest that EMMPRIN mRNA and protein levels in the fibrotic livers are lower than those in the corresponding normal control livers, but higher SNO level of EMMPRIN in fibrotic liver area was shown by immunohistochemistry, immunofluorescence staining, and biotin-switch assay conversely . Primary EMMPRIN comes from hepatocytes and liver sinus epithelial cells (LSECs) rather than quiescent HSCs. To mimic the uptake of extrinsic EMMPRIN, supernatants from mouse primary hepatocytes/293 cells transfected with EMMPRIN wild-type plasmids (WT) and EMMPRIN SNO site (cysteine 87) mutation plasmids (MUT) were collected and added to JS-1/LX2 cell medium. The MUT EMMPRIN diminishes SNO successfully, enhances the activities of MMP2 and MMP9, and subsequently increases HSC migration. In conclusion, SNO of EMMPRIN influences HSC migration and MMP activities in liver fibrosis. This finding may shed light on the possible regulatory mechanism of MMPs in ECM accumulation in liver fibrosis.

References

Jiao J, Friedman S, Aloman C . Hepatic fibrosis. Curr Opin Gastroenterol. 2009; 25(3):223-9. PMC: 2883289. DOI: 10.1097/mog.0b013e3283279668. View

Robert S, Gicquel T, Victoni T, Valenca S, Barreto E, Bailly-Maitre B . Involvement of matrix metalloproteinases (MMPs) and inflammasome pathway in molecular mechanisms of fibrosis. Biosci Rep. 2016; 36(4). PMC: 4945993. DOI: 10.1042/BSR20160107. View

Rizza S, Di Leo L, Mandatori S, De Zio D, Filomeni G . Mitophagy contributes to alpha-tocopheryl succinate toxicity in GSNOR-deficient hepatocellular carcinoma. Biochem Pharmacol. 2020; 176:113885. DOI: 10.1016/j.bcp.2020.113885. View

Zhang D, Zhao Y, Wei D, Li Y, Zhang Y, Wu J . HAb18G/CD147 promotes activation of hepatic stellate cells and is a target for antibody therapy of liver fibrosis. J Hepatol. 2012; 57(6):1283-91. DOI: 10.1016/j.jhep.2012.07.042. View

Yan Z, Qu K, Zhang J, Huang Q, Qu P, Xu X . CD147 promotes liver fibrosis progression via VEGF-A/VEGFR2 signalling-mediated cross-talk between hepatocytes and sinusoidal endothelial cells. Clin Sci (Lond). 2015; 129(8):699-710. DOI: 10.1042/CS20140823. View

Sangwung P, Greco T, Wang Y, Ischiropoulos H, Sessa W, Iwakiri Y . Proteomic identification of S-nitrosylated Golgi proteins: new insights into endothelial cell regulation by eNOS-derived NO. PLoS One. 2012; 7(2):e31564. PMC: 3283662. DOI: 10.1371/journal.pone.0031564. View

Ravichandra A, Schwabe R . Mouse Models of Liver Fibrosis. Methods Mol Biol. 2021; 2299:339-356. DOI: 10.1007/978-1-0716-1382-5_23. View

Hess D, Matsumoto A, Kim S, Marshall H, Stamler J . Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol. 2005; 6(2):150-66. DOI: 10.1038/nrm1569. View

Li H, Ju D, Zhang D, Li H, Kong L, Guo Y . Activation of TGF-β1-CD147 positive feedback loop in hepatic stellate cells promotes liver fibrosis. Sci Rep. 2015; 5:16552. PMC: 4642271. DOI: 10.1038/srep16552. View

10.

Iwakiri Y, Kim M . Nitric oxide in liver diseases. Trends Pharmacol Sci. 2015; 36(8):524-36. PMC: 4532625. DOI: 10.1016/j.tips.2015.05.001. View

11.

Tu T, Calabro S, Lee A, Maczurek A, Budzinska M, Warner F . Hepatocytes in liver injury: Victim, bystander, or accomplice in progressive fibrosis?. J Gastroenterol Hepatol. 2015; 30(12):1696-704. DOI: 10.1111/jgh.13065. View

12.

Iwakiri Y . S-nitrosylation of proteins: a new insight into endothelial cell function regulated by eNOS-derived NO. Nitric Oxide. 2011; 25(2):95-101. PMC: 3152628. DOI: 10.1016/j.niox.2011.04.014. View

13.

Pautz A, Art J, Hahn S, Nowag S, Voss C, Kleinert H . Regulation of the expression of inducible nitric oxide synthase. Nitric Oxide. 2010; 23(2):75-93. DOI: 10.1016/j.niox.2010.04.007. View

14.

Bai Y, Huang W, Ma L, Jiang J, Chen Z . Importance of N-glycosylation on CD147 for its biological functions. Int J Mol Sci. 2014; 15(4):6356-77. PMC: 4013633. DOI: 10.3390/ijms15046356. View

15.

Iwakiri Y . Nitric oxide in liver fibrosis: The role of inducible nitric oxide synthase. Clin Mol Hepatol. 2016; 21(4):319-25. PMC: 4712158. DOI: 10.3350/cmh.2015.21.4.319. View

16.

Saxena D, Oh-oka T, Kadomatsu K, Muramatsu T, Toshimori K . Behaviour of a sperm surface transmembrane glycoprotein basigin during epididymal maturation and its role in fertilization in mice. Reproduction. 2002; 123(3):435-44. DOI: 10.1530/rep.0.1230435. View

17.

Rodriguez-Ortigosa C, Celay J, Olivas I, Juanarena N, Arcelus S, Uriarte I . A GAPDH-mediated trans-nitrosylation pathway is required for feedback inhibition of bile salt synthesis in rat liver. Gastroenterology. 2014; 147(5):1084-93. DOI: 10.1053/j.gastro.2014.07.030. View

18.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

19.

Wei W, Li B, Hanes M, Kakar S, Chen X, Liu L . S-nitrosylation from GSNOR deficiency impairs DNA repair and promotes hepatocarcinogenesis. Sci Transl Med. 2010; 2(19):19ra13. PMC: 3085984. DOI: 10.1126/scitranslmed.3000328. View

20.

Egawa N, Koshikawa N, Tomari T, Nabeshima K, Isobe T, Seiki M . Membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) cleaves and releases a 22-kDa extracellular matrix metalloproteinase inducer (EMMPRIN) fragment from tumor cells. J Biol Chem. 2006; 281(49):37576-85. DOI: 10.1074/jbc.M606993200. View