DOI QR코드

DOI QR Code

Ginseng-derived type I rhamnogalacturonan polysaccharide binds to galectin-8 and antagonizes its function

  • Yi Zheng (Engineering Research Center of Glycoconjugates Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University) ;
  • Yunlong Si (Engineering Research Center of Glycoconjugates Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University) ;
  • Xuejiao Xu (Engineering Research Center of Glycoconjugates Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University) ;
  • Hongming Gu (Engineering Research Center of Glycoconjugates Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University) ;
  • Zhen He (Engineering Research Center of Glycoconjugates Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University) ;
  • Zihan Zhao (Engineering Research Center of Glycoconjugates Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University) ;
  • Zhangkai Feng (Engineering Research Center of Glycoconjugates Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University) ;
  • Jiyong Su (Engineering Research Center of Glycoconjugates Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University) ;
  • Kevin H. Mayo (Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota) ;
  • Yifa Zhou (Engineering Research Center of Glycoconjugates Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University) ;
  • Guihua Tai (Engineering Research Center of Glycoconjugates Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University)
  • Received : 2023.07.29
  • Accepted : 2023.11.29
  • Published : 2024.03.01

Abstract

Background: Panax ginseng Meyer polysaccharides exhibit various biological functions, like antagonizing galectin-3-mediated cell adhesion and migration. Galectin-8 (Gal-8), with its linker-joined N- and C-terminal carbohydrate recognition domains (CRDs), is also crucial to these biological processes, and thus plays a role in various pathological disorders. Yet the effect of ginseng-derived polysaccharides in modulating Gal-8 function has remained unclear. Methods: P. ginseng-derived pectin was chromatographically isolated and enzymatically digested to obtain a series of polysaccharides. Biolayer Interferometry (BLI) quantified their binding affinity to Gal-8, and their inhibitory effects on Gal-8 was assessed by hemagglutination, cell migration and T-cell apoptosis. Results: Our ginseng-derived pectin polysaccharides consist mostly of rhamnogalacturonan-I (RG-I) and homogalacturonan (HG). BLI shows that Gal-8 binding rests primarily in RG-I and its β-1,4-galactan side chains, with sub-micromolar KD values. Both N- and C-terminal Gal-8 CRDs bind RG-I, with binding correlated with Gal-8-mediated function. Conclusion: P. ginseng RG-I pectin β-1,4-galactan side chains are crucial to binding Gal-8 and antagonizing its function. This study enhances our understanding of galectin-sugar interactions, information that may be used in the development of pharmaceutical agents targeting Gal-8.

Keywords

Acknowledgement

This work was supported by the National Natural Science Foundation of China (grant numbers 32171276 and 31870796).

References

  1. Hu Y, He Y, Niu Z, Shen T, Zhang J, Wang X, Hu W, Cho JY. A review of the immunomodulatory activities of polysaccharides isolated from Panax species. J Ginseng Res 2022;46(1):23-32. https://doi.org/10.1016/j.jgr.2021.06.003
  2. Tao R, Lu K, Zong G, Xia Y, Han H, Zhao Y, Wei Z, Lu Y. Ginseng polysaccharides: potential antitumor agents. J Ginseng Res 2023;47(1):9-22. https://doi.org/10.1016/j.jgr.2022.07.002
  3. Lee JH, Shim JS, Lee JS, Kim MK, Chung MS, Kim KH. Pectin-like acidic polysaccharide from Panax ginseng with selective antiadhesive activity against pathogenic bacteria. Carbohydr Res 2006;341(9):1154-63. https://doi.org/10.1016/j.carres.2006.03.032
  4. Chen F, Huang G. Antioxidant activity of polysaccharides from different sources of ginseng. Int J Biol Macromol 2019;125:906-8. https://doi.org/10.1016/j.ijbiomac.2018.12.134
  5. Sun C, Chen Y, Li X, Tai G, Fan Y, Zhou Y. Anti-hyperglycemic and anti-oxidative activities of ginseng polysaccharides in STZ-induced diabetic mice. Food Funct 2014;5:845-8. https://doi.org/10.1039/c3fo60326a
  6. Zhang X, Yu L, Bi H, Li X, Ni W, Han H, Li N, Wang B, Zhou Y, Tai G. Total fractionation and characterization of the water-soluble polysaccharides isolated from Panax ginseng C. A. Meyer. Carbohydr Polym 2009;77(3):544-52. https://doi.org/10.1016/j.carbpol.2009.01.034
  7. Yu L, Zhang X, Li S, Liu X, Sun L, Liu H, Iteku J, Zhou Y, Tai G. Rhamnogalacturonan I domains from ginseng pectin. Carbohydr Polym 2010;79 (4):811-7. https://doi.org/10.1016/j.carbpol.2009.08.028
  8. Sun L, Ropartz D, Cui L, Shi H, Ralet MC, Zhou Y. Structural characterization of rhamnogalacturonan domains from Panax ginseng C. A. Meyer. Carbohydr Polym 2019;203:119-27. https://doi.org/10.1016/j.carbpol.2018.09.045
  9. Wang J, Li S, Fan Y, Chen Y, Liu D, Cheng H, Gao X, Zhou Y. Anti-fatigue activity of the water-soluble polysaccharides isolated from Panax ginseng C. A. Meyer. J Ethnopharmacol 2010;130:421-3. https://doi.org/10.1016/j.jep.2010.05.027
  10. Glinsky VV, Raz A. Modified citrus pectin anti-metastatic properties: one bullet, multiple targets. Carbohydr Res 2009;344(14):1788-91. https://doi.org/10.1016/j.carres.2008.08.038
  11. Thijssen VL, Rabinovich GA, Griffioen AW. Vascular galectins: regulators of tumor progression and targets for cancer therapy. Cytokine Growth Factor Rev 2013;24 (6):547-58. https://doi.org/10.1016/j.cytogfr.2013.07.003
  12. Toscano MA, Martinez Allo VC, Cutine AM, Rabinovich GA, Marino KV. Untangling galectin-driven regulatory circuits in autoimmune inflammation. Trends Mol Med 2018;24(4):348-63. https://doi.org/10.1016/j.molmed.2018.02.008
  13. Mendez-Huergo SP, Blidner AG, Rabinovich GA. Galectins: emerging regulatory checkpoints linking tumor immunity and angiogenesis. Curr Opin Immunol 2017; 45:8-15. https://doi.org/10.1016/j.coi.2016.12.003
  14. Inohara H, Raz A. Effects of natural complex carbohydrate (citrus pectin) on murine melanoma cell properties related to galectin-3 functions. GIycoconjugate J 1994;11:527-32. https://doi.org/10.1007/BF00731303
  15. Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R, Raz A. Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin. J Natl Cancer Inst 2002;94(24):1854-62. https://doi.org/10.1093/jnci/94.24.1854
  16. Gunning AP, Bongaerts RJ, Morris VJ. Recognition of galactan components of pectin by galectin-3. Faseb J 2009;23(2):415-24. https://doi.org/10.1096/fj.08-106617
  17. Streetly MJ, Maharaj L, Joel S, Schey SA, Gribben JG, Cotter FE. GCS-100, a novel galectin-3 antagonist, modulates MCL-1, NOXA, and cell cycle to induce myeloma cell death. Blood 2010;115:3939-48. https://doi.org/10.1182/blood-2009-10-251660
  18. Gao X, Zhi Y, Sun L, Peng X, Zhang T, Xue H, Tai G, Zhou Y. The inhibitory effects of a rhamnogalacturonan I (RG-I) domain from ginseng pectin on galectin-3 and its structure-activity relationship. J Biol Chem 2013;288(47):33953-65. https://doi.org/10.1074/jbc.M113.482315
  19. Zhang L, Wang P, Qin Y, Cong Q, Shao C, Du Z, Ni X, Li P, Ding K. RN1, a novel galectin-3 inhibitor, inhibits pancreatic cancer cell growth in vitro and in vivo via blocking galectin-3 associated signaling pathways. Oncogene 2017;36:1297-308. https://doi.org/10.1038/onc.2016.306
  20. Xue H, Zhao Z, Lin Z, Geng J, Guan Y, Song C, Zhou Y, Tai G. Selective effects of ginseng pectins on galectin-3-mediated T cell activation and apoptosis. Carbohydr Polym 2019;219:121-9. https://doi.org/10.1016/j.carbpol.2019.05.023
  21. Zhou L, Ma P, Shuai M, Huang J, Sun C, Yao X, Chen Z, Min X, Zhang T. Analysis of the water-soluble polysaccharides from Camellia japonica pollen and their inhibitory effects on galectin-3 function. Int J Biol Macromol 2020;159:455-60. https://doi.org/10.1016/j.ijbiomac.2020.05.051
  22. Pan X, Wang H, Zheng Z, Huang X, Yang L, Liu J, Wang K, Zhang Y. Pectic polysaccharide from Smilax China L. ameliorated ulcerative colitis by inhibiting the galectin-3/NLRP3 inflammasome pathway. Carbohydr Polym 2022;277: 118864.
  23. Hadari YR, Arbel-Goren R, Levy Y, Amsterdam A, Alon R, Zakut R, Zick Y. Galectin8 binding to integrins inhibits cell adhesion and induces apoptosis. J Cell Sci 2000; 113:2385-97. https://doi.org/10.1242/jcs.113.13.2385
  24. Stowell SR, Arthur CM, Slanina KA, Horton JR, Smith DF, Cummings RD. Dimeric Galectin-8 induces phosphatidylserine exposure in leukocytes through polylactosamine recognition by the C-terminal domain. J Biol Chem 2008;283(29): 20547-59. https://doi.org/10.1074/jbc.M802495200
  25. Ideo H, Matsuzaka T, Nonaka T, Seko A, Yamashita K. Galectin-8-N-domain recognition mechanism for sialylated and sulfated glycans. J Biol Chem 2011;286 (13):11346-55. https://doi.org/10.1074/jbc.M110.195925
  26. Troncoso MF, Ferragut F, Bacigalupo ML, Cardenas Delgado VM, Nugnes LG, Gentilini L, Laderach D, Wolfenstein-Todel C, Compagno D, Rabinovich GA, Elola MT. Galectin-8: a matricellular lectin with key roles in angiogenesis. Glycobiology 2014;24(10):907-14. https://doi.org/10.1093/glycob/cwu054
  27. Stowell SR, Arthur CM, Dias-Baruffi M, Rodrigues LC, Gourdine JP, HeimburgMolinaro J, Ju T, Molinaro RJ, Rivera-Marrero C, Xia B, Smith DF, Cummings RD. Innate immune lectins kill bacteria expressing blood group antigen. Nat Med 2010; 16(3):295-301. https://doi.org/10.1038/nm.2103
  28. Norambuena A, Metz C, Vicuna L, Silva A, Pardo E, Oyanadel C, Massardo L, Gonzalez A, Soza A. Galectin-8 induces apoptosis in Jurkat T cells by phosphatidic acid-mediated ERK1/2 activation supported by protein kinase A down-regulation. J Biol Chem 2009;284(19):12670-9. https://doi.org/10.1074/jbc.M808949200
  29. Zhang M, Zu H, Zhuang X, Yu Y, Wang Y, Zhao Z, Zhou Y. Structural analyses of the HG-type pectin from notopterygium incisum and its effects on galectins. Int J Biol Macromol 2020;162:1035-43. https://doi.org/10.1016/j.ijbiomac.2020.06.216
  30. Stegmayr J, Lepur A, Kahl-Knutson B, Aguilar-Moncayo M, Klyosov AA, Field RA, Oredsson S, Nilsson UJ, Leffler H. Low or No inhibitory potency of the canonical galectin carbohydrate-binding site by pectins and galactomannans. J Biol Chem 2016;291(25):13318-34. https://doi.org/10.1074/jbc.M116.721464
  31. Si Y, Wang Y, Gao J, Song C, Feng S, Zhou Y, Tai G, Su J. Crystallization of galectin8 linker reveals intricate relationship between the N-terminal tail and the linker. Int J Mol Sci 2016;17(12):2088.
  32. Zhang T, Zheng Y, Zhao D, Yan J, Sun C, Zhou Y, Tai G. Multiple approaches to assess pectin binding to galectin-3. Int J Biol Macromol 2016;91:994-1001. https://doi.org/10.1016/j.ijbiomac.2016.06.058
  33. Xue H, Liu L, Zhao Z, Zhang Z, Guan Y, Cheng H, Zhou Y, Tai G. The N-terminal tail coordinates with carbohydrate recognition domain to mediate galectin-3 induced apoptosis in T cells. Oncotarget 2017;8:49824-38. https://doi.org/10.18632/oncotarget.17760
  34. Mohnen D. Pectin structure and biosynthesis. Curr Opin Plant Biol 2008;11(3): 266-77. https://doi.org/10.1016/j.pbi.2008.03.006
  35. Ding H, Cui S, Goff H, Chen J, Wang Q, Han N. Arabinan-rich rhamnogalacturonanI from flaxseed kernel cell wall. Food Hydrocolloids 2015;47:158-67. https://doi.org/10.1016/j.foodhyd.2015.01.011
  36. Guo Q, Cui SW, Kang J, Ding H, Wang Q, Wang C. Non-starch polysaccharides from American ginseng: physicochemical investigation and structural characterization. Food Hydrocolloids 2015;44:320-7. https://doi.org/10.1016/j.foodhyd.2014.09.031
  37. Norambuena A, Metz C, Vicuna L, Silva A, Pardo E, Oyanadel C, Massardo L, Gonzalez A, Soza A. Galectin-8 induces apoptosis in Jurkat T cells by phosphatidic acid-mediated ERK1/2 activation supported by protein kinase A down-regulation. J Biol Chem 2009;284:12670-9. https://doi.org/10.1074/jbc.M808949200
  38. Zhang T, Lan Y, Zheng Y, Liu F, Zhao D, Mayo KH, Zhou Y, Tai G. Identification of the bioactive components from pH-modified citrus pectin and their inhibitory effects on galectin-3 function. Food Hydrocolloids 2016;58:113-9. https://doi.org/10.1016/j.foodhyd.2016.02.020
  39. Marino KV, Cagnoni AJ, Croci DO, Rabinovich GA. Targeting galectin-driven regulatory circuits in cancer and fibrosis. Nat Rev Drug Discov 2023;22:295-316. https://doi.org/10.1038/s41573-023-00636-2
  40. Kruk L, Braun A, Cosset E, Gudermann T, Mammadova-Bach E. Galectin functions in cancer-associated inflammation and thrombosis. Front Cardiovasc Med 2023;10: 1052959. https://doi.org/10.3389/fcvm.2023.1052959.