Abstract
Histidine phosphorylation (pHis) was first reported in 1962. There are few studies on pHis because of the thermal and acidic instability of pHis and the lack of specific methods to detect it. pHis has two isomers of 1-phosphate histidine (1-pHis) and 3-phosphate histidine (3-pHis). pHis antibodies have been developed recently and have promoted research in this field. In this study, we established a CCl4-induced liver fibrosis model in C57 mice and a TGF-β1-induced HSC activation model in LX-2 cells, to study the role of histidine phosphorylation. The expression of histidine kinases NME1 and NME2 was increased, histidine phosphatase PGAM5 and PHPT1 was unchanged, and 1-pHis and 3-pHis were increased in the in vivo and in vitro models. The expression of LHPP was decreased in the in vivo model but not in the in vitro model. To further study the role of NME1, NME2, and histidine phosphorylation in HSC activation, we silenced NME1 or NME2 and administered TGF-β1 in LX-2 cells. The results showed silencing NME1 or NME2 decreased TGF-β1-induced pHis levels and the expression of α-SMA and COL1A1, indicating the activation of HSC was suppressed. Then, we found the inhibitory effect on HSC activation is due to reduced phosphorylation of Smad2 and Smad3. In summary, our studies indicate that NME1 and NME2 are involved in TGF-β1-induced HSC activation and CCl4-induced liver fibrosis, which may be mediated by histidine phosphorylation.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adam K, Hunter T (2018) Histidine kinases and the missing phosphoproteome from prokaryotes to eukaryotes. Lab Invest 98:233–247. https://doi.org/10.1038/labinvest.2017.118
Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M (2019) From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol 16:411–428. https://doi.org/10.1038/s41575-019-0145-7
Boissan M, Schlattner U, Lacombe ML (2018) The NDPK/NME superfamily: state of the art. Lab Invest 98:164–174. https://doi.org/10.1038/labinvest.2017.137
Boyer PD, Deluca M, Ebner KE, Hultquist DE, Peter JB (1962) Identification of phosphohistidine in digests from a probable intermediate of oxidative phosphorylation. J Biol Chem 237:PC3306–PC3308
Dewidar B, Meyer C, Dooley S, Meindl-Beinker AN (2019) TGF-beta in hepatic stellate cell activation and liver fibrogenesis-updated 2019. Cells 8:1419. https://doi.org/10.3390/cells8111419
Fagone P, Mangano K, Pesce A, Portale TR, Puleo S, Nicoletti F (2016) Emerging therapeutic targets for the treatment of hepatic fibrosis. Drug Discov Today 21:369–375. https://doi.org/10.1016/j.drudis.2015.10.015
Fuhs SR, Hunter T (2017) PHisphorylation: the emergence of histidine phosphorylation as a reversible regulatory modification. Curr Opin Cell Biol 45:8–16. https://doi.org/10.1016/j.ceb.2016.12.010
Fuhs SR, Meisenhelder J, Aslanian A, Ma L, Zagorska A, Stankova M, Alan B, Obeidi FA, Mauger J, Lemka G, Yates JR, Hunter T (2015) Monoclonal 1- and 3-phosphohistidine antibodies: new tools to study histidine phosphorylation. Cell 162:198–210. https://doi.org/10.1016/j.cell.2015.05.046
Gandhi CR (2017) Hepatic stellate cell activation and pro-fibrogenic signals. J Hepatol 67:1104–1105. https://doi.org/10.1016/j.jhep.2017.06.001
Groeneveldt C, van Hall T, van der Burg SH, Ten DP, van Montfoort N (2020) Immunotherapeutic potential of TGF-beta inhibition and oncolytic viruses. Trends Immunol 41:406–420. https://doi.org/10.1016/j.it.2020.03.003
Hinduper SK, Colombi M, Fuhs SR, Matter MS, Guri Y, Adam K, Cornu M, Piscuoglio S, Kyng C, Betz C, Liko D, Quagliata L, Moes S, Jenoe P, Terracciano LM, Heim MH, Hunter T, Hall MN (2018) The protein histidine phosphatase LHPP is a tumour suppressor. Nature 555:678–682. https://doi.org/10.1038/nature26140
Huynh LK, Hipolito CJ, Ten DP (2019) A perspective on the development of TGF-beta inhibitors for cancer treatment. Biomolecules 9:743. https://doi.org/10.3390/biom9110743
Kee JM, Villani B, Carpenter LR, Muir TW (2010) Development of stable phosphohistidine analogues. J Am Chem Soc 132:14327–14329. https://doi.org/10.1021/ja104393t
Khan I, Steeg PS (2018) The relationship of NM23 (NME) metastasis suppressor histidine phosphorylation to its nucleoside diphosphate kinase, histidine protein kinase and motility suppression activities. Oncotarget 9:10185–10202. https://doi.org/10.18632/oncotarget.23796
Koyama Y, Brenner DA (2017) Liver inflammation and fibrosis. J Clin Invest 127:55–64. https://doi.org/10.1172/JCI88881
Lapek JJ, Tombline G, Friedman AE (2011) Mass spectrometry detection of histidine phosphorylation on NM23-H1. J Proteome Res 10:751–755. https://doi.org/10.1021/pr100905m
Larson C, Oronsky B, Carter CA, Oronsky A, Knox SJ, Sher D, Reid TR (2020) TGF-beta: a master immune regulator. Expert Opin Ther Targets 24:427–438. https://doi.org/10.1080/14728222.2020.1744568
Lee PW, Severin ME, Lovett-Racke AE (2017) TGF-beta regulation of encephalitogenic and regulatory T cells in multiple sclerosis. Eur J Immunol 47:446–453. https://doi.org/10.1002/eji.201646716
Lee YA, Wallace MC, Friedman SL (2015) Pathobiology of liver fibrosis: a translational success story. Gut 64:830–841. https://doi.org/10.1136/gutjnl-2014-306842
Liu X, Xu J, Brenner DA, Kisseleva T (2013) Reversibility of liver fibrosis and inactivation of fibrogenic myofibroblasts. Curr Pathobiol Rep 1:209–214. https://doi.org/10.1007/s40139-013-0018-7
Marino N, Nakayama J, Collins JW, Steeg PS (2012) Insights into the biology and prevention of tumor metastasis provided by the Nm23 metastasis suppressor gene. Cancer Metastasis Rev 31:593–603. https://doi.org/10.1007/s10555-012-9374-8
Matsumura T, Suzuki T, Aizawa K, Sawaki D, Munemasa Y, Ishida J, Nagai R (2009) Regulation of transforming growth factor-beta-dependent cyclooxygenase-2 expression in fibroblasts. J Biol Chem 284:35861–35871. https://doi.org/10.1074/jbc.M109.014639
Matthews HR (1995) Protein kinases and phosphatases that act on histidine, lysine, or arginine residues in eukaryotic proteins: a possible regulator of the mitogen-activated protein kinase cascade. Pharmacol Ther 67:323–350. https://doi.org/10.1016/0163-7258(95)00020-8
Meng XM, Nikolic-Paterson DJ, Lan HY (2016) TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol 12:325–338. https://doi.org/10.1038/nrneph.2016.48
Morikawa M, Derynck R, Miyazono K (2016) TGF-beta and the TGF-beta family: context-dependent roles in cell and tissue physiology. Cold Spring Harb Perspect Biol 8:a021873. https://doi.org/10.1101/cshperspect.a021873
Nicoletti F, Di Marco R, Patti F, Reggio E, Nicoletti A, Zaccone P, Stivala F, Meroni PL, Reggio A (1998) Blood levels of transforming growth factor-beta 1 (TGF-beta1) are elevated in both relapsing remitting and chronic progressive multiple sclerosis (MS) patients and are further augmented by treatment with interferon-beta 1b (IFN-beta1b). Clin Exp Immunol 113:96–99. https://doi.org/10.1046/j.1365-2249.1998.00604.x
Panda S, Srivastava S, Li Z, Vaeth M, Fuhs SR, Hunter T, Skolnik EY (2016) Identification of PGAM5 as a mammalian protein histidine phosphatase that plays a central role to negatively regulate CD4(+) t cells. Mol Cell 63:457–469. https://doi.org/10.1016/j.molcel.2016.06.021
Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA (2014) Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol 14:181–194. https://doi.org/10.1038/nri3623
Potel CM, Lin MH, Prust N, van den Toorn H, Heck A, Lemeer S (2019) Gaining confidence in the elusive histidine phosphoproteome. Anal Chem 91:5542–5547. https://doi.org/10.1021/acs.analchem.9b00734
Seki E, Schwabe RF (2015) Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 61:1066–1079. https://doi.org/10.1002/hep.27332
Seong HA, Jung H, Ha H (2007) NM23-H1 tumor suppressor physically interacts with serine-threonine kinase receptor-associated protein, a transforming growth factor-beta (TGF-beta) receptor-interacting protein, and negatively regulates TGF-beta signaling. J Biol Chem 282:12075–12096. https://doi.org/10.1074/jbc.M609832200
Srivastava S, Zhdanova O, Di L, Li Z, Albaqumi M, Wulff H, Skolnik EY (2008) Protein histidine phosphatase 1 negatively regulates CD4 T cells by inhibiting the K+ channel KCa3.1. Proc Natl Acad Sci USA 105:14442–14446. https://doi.org/10.1073/pnas.0803678105
Tacke F, Trautwein C (2015) Mechanisms of liver fibrosis resolution. J Hepatol 63:1038–1039. https://doi.org/10.1016/j.jhep.2015.03.039
Zhang Y, Alexander PB, Wang XF (2017) TGF-beta family signaling in the control of cell proliferation and survival. Cold Spring Harb Perspect Biol 9:a022145. https://doi.org/10.1101/cshperspect.a022145
Zhao RZ, Gong L, Li L, Guo LL, Zhu DX, Wu ZH, Zhou QH (2013) Nm23-H1 is a negative regulator of TGF-beta1-dependent induction of epithelial-mesenchymal transition. Exp Cell Res 319:740–749. https://doi.org/10.1016/j.yexcr.2012.10.013
Funding
This study was supported by the New Xiangya Talent Project of the Third Xiangya Hospital of Central South University (No. 20170308) and the Fundamental Research Funds for the Central Universities of Central South University (No. 2019zzts826).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Gong, H., Fan, Z., Yi, D. et al. Histidine kinase NME1 and NME2 are involved in TGF-β1-induced HSC activation and CCl4-induced liver fibrosis. J Mol Hist 51, 573–581 (2020). https://doi.org/10.1007/s10735-020-09906-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10735-020-09906-4