Galectin-9 Explained

Galectin-9 was first isolated from mouse embryonic kidney in 1997 as a 36 kDa beta-galactoside lectin protein.^[1] Human galectin-9 is encoded by the LGALS9 gene.^{[2] [3]}

Function

The protein has N- and C- terminal carbohydrate-binding domains connected by a link peptide. Multiple alternatively spliced transcript variants have been found for this gene.

Galectin-9 is one of the most studied ligands for HAVCR2 (TIM-3) and is expressed on various tumor cells. However, it can also interact with other proteins (CLEC7A,^[4] CD137,^[5] CD40^[6]). For example, an interaction with CD40 on T-cells inhibits their proliferation and induces cell death.

Galectin-9 also has important cytoplasmic, intracellular functions and controls AMPK^{[7] [8]} in response to lysosomal damage that can occur upon exposure to endogenous and exogenous membrane damaging agents such as crystalline silica, cholesterol crystals, microbial toxins, proteopathic aggregates such as tau fibrils and amyloids, and signaling pathways inducing lysosomal permeabilization such as those initiated by TRAIL.^[9] Mild lysosomal damage, such as that caused by the anti-diabetes drug metformin may contribute to the therapeutic action of metformin by activating AMPK. The mechanism of how Galectin-9 activates AMPK involves recognition of exposed lysosomal lumenal glycoproteins such as LAMP1, LAMP2, SCRAB2, TMEM192, etc., repulsion of deubiquitinating enzyme USP9X, increased K63 ubiquitination of TAK1 (MAP3K7) kinase, which in turn phopshorylates AMPK and activates it. This signaling cascade directly links Galectin-9 intracellular function with ubiqutin systems. Galectin-9, through its regulation of AMPK, a kinase that negatively regulates mTOR, cooperates with Galectin-8-based effects to inactivate mTOR downstream of the lysosomal damaging agents and conditions.

Clinical significance

The expression of galectin-9 has been detected on various hematological malignancies, such as CLL,^[10] MDS,^[11] Hodgkin's lymphomas,^[12] AML^[13] or solid tumors, such as lung cancer,^[14] breast cancer,^[15] and hepatocellular carcinoma.^[16]

HAVCR2/ galectin-9 interaction attenuated T-cell expansion and effectors function in tumor microenvironment and chronic infections.^[17] Moreover, galectin-9 contributed to tumorigenesis by tumor cell transformation, cell-cycle regulation, angiogenesis, and cell adhesion.^[18] The correlative studies analyzing the expression of galectin-9 and malignant clinical features showed controversial results. This can be explained as that galectin-9 can promote tumor immune escape as well as inhibit metastasis by promoting endothelial adhesion.^[16] Therefore many factors such as tumor type, stage, and the involvement of different galectins should be take into consideration when correlating the expression level and the malignancy.

Galectin-9, through its cytoplasmic action in control of AMPK, may affect various health conditions impacted by AMPK, including metabolism, obesity, diabetes, cancer, immune responses, and may be a part of the mechanism of action of the widely-prescribed anti-diabetes drug metformin.

Further reading

• Hirashima M, Kashio Y, Nishi N, Yamauchi A, Imaizumi TA, Kageshita T, Saita N, Nakamura T . Galectin-9 in physiological and pathological conditions . Glycoconjugate Journal . 19 . 7–9 . 593–600 . 2004 . 14758084 . 10.1023/B:GLYC.0000014090.63206.2f . 11006101 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Matsumoto R, Matsumoto H, Seki M, Hata M, Asano Y, Kanegasaki S, Stevens RL, Hirashima M . Human ecalectin, a variant of human galectin-9, is a novel eosinophil chemoattractant produced by T lymphocytes . The Journal of Biological Chemistry . 273 . 27 . 16976–84 . July 1998 . 9642261 . 10.1074/jbc.273.27.16976 . free .
• Matsumoto R, Hirashima M, Kita H, Gleich GJ . Biological activities of ecalectin: a novel eosinophil-activating factor . Journal of Immunology . 168 . 4 . 1961–7 . February 2002 . 11823532 . 10.4049/jimmunol.168.4.1961 . free .
• Kageshita T, Kashio Y, Yamauchi A, Seki M, Abedin MJ, Nishi N, Shoji H, Nakamura T, Ono T, Hirashima M . Possible role of galectin-9 in cell aggregation and apoptosis of human melanoma cell lines and its clinical significance . International Journal of Cancer . 99 . 6 . 809–16 . June 2002 . 12115481 . 10.1002/ijc.10436 . 205934076 . free .
• Imaizumi T, Kumagai M, Sasaki N, Kurotaki H, Mori F, Seki M, Nishi N, Fujimoto K, Tanji K, Shibata T, Tamo W, Matsumiya T, Yoshida H, Cui XF, Takanashi S, Hanada K, Okumura K, Yagihashi S, Wakabayashi K, Nakamura T, Hirashima M, Satoh K . Interferon-gamma stimulates the expression of galectin-9 in cultured human endothelial cells . Journal of Leukocyte Biology . 72 . 3 . 486–91 . September 2002 . 10.1189/jlb.72.3.486 . 12223516 . 17010289 .
• Asakura H, Kashio Y, Nakamura K, Seki M, Dai S, Shirato Y, Abedin MJ, Yoshida N, Nishi N, Imaizumi T, Saita N, Toyama Y, Takashima H, Nakamura T, Ohkawa M, Hirashima M . Selective eosinophil adhesion to fibroblast via IFN-gamma-induced galectin-9 . Journal of Immunology . 169 . 10 . 5912–8 . November 2002 . 12421975 . 10.4049/jimmunol.169.10.5912 . free .
• Kashio Y, Nakamura K, Abedin MJ, Seki M, Nishi N, Yoshida N, Nakamura T, Hirashima M . Galectin-9 induces apoptosis through the calcium-calpain-caspase-1 pathway . Journal of Immunology . 170 . 7 . 3631–6 . April 2003 . 12646627 . 10.4049/jimmunol.170.7.3631 . free .
• Abedin MJ, Kashio Y, Seki M, Nakamura K, Hirashima M . Potential roles of galectins in myeloid differentiation into three different lineages . Journal of Leukocyte Biology . 73 . 5 . 650–6 . May 2003 . 12714580 . 10.1189/jlb.0402163 . 21337581 .
• Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y, Doi T, Shimotohno K, Harada T, Nishida E, Hayashi H, Sugano S . Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways . Oncogene . 22 . 21 . 3307–18 . May 2003 . 12761501 . 10.1038/sj.onc.1206406 . 38880905 .
• Irie A, Yamauchi A, Kontani K, Kihara M, Liu D, Shirato Y, Seki M, Nishi N, Nakamura T, Yokomise H, Hirashima M . Galectin-9 as a prognostic factor with antimetastatic potential in breast cancer . Clinical Cancer Research . 11 . 8 . 2962–8 . April 2005 . 15837748 . 10.1158/1078-0432.CCR-04-0861 . 15041189 .
• Kasamatsu A, Uzawa K, Nakashima D, Koike H, Shiiba M, Bukawa H, Yokoe H, Tanzawa H . Galectin-9 as a regulator of cellular adhesion in human oral squamous cell carcinoma cell lines . International Journal of Molecular Medicine . 16 . 2 . 269–73 . August 2005 . 16012760 . 10.3892/ijmm.16.2.269 .
• Dai SY, Nakagawa R, Itoh A, Murakami H, Kashio Y, Abe H, Katoh S, Kontani K, Kihara M, Zhang SL, Hata T, Nakamura T, Yamauchi A, Hirashima M . Galectin-9 induces maturation of human monocyte-derived dendritic cells . Journal of Immunology . 175 . 5 . 2974–81 . September 2005 . 16116184 . 10.4049/jimmunol.175.5.2974 . free .
• Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK . The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity . Nature Immunology . 6 . 12 . 1245–52 . December 2005 . 16286920 . 10.1038/ni1271 . 24886582 .
• van de Weyer PS, Muehlfeit M, Klose C, Bonventre JV, Walz G, Kuehn EW . A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9 . Biochemical and Biophysical Research Communications . 351 . 2 . 571–6 . December 2006 . 17069754 . 10.1016/j.bbrc.2006.10.079 .

Notes and References

1. Wada J, Kanwar YS . Identification and characterization of galectin-9, a novel beta-galactoside-binding mammalian lectin . The Journal of Biological Chemistry . 272 . 9 . 6078–86 . February 1997 . 9038233 . 10.1074/jbc.272.9.6078. free .
2. Türeci O, Schmitt H, Fadle N, Pfreundschuh M, Sahin U . Molecular definition of a novel human galectin which is immunogenic in patients with Hodgkin's disease . The Journal of Biological Chemistry . 272 . 10 . 6416–22 . March 1997 . 9045665 . 10.1074/jbc.272.10.6416 . free .
3. Web site: Entrez Gene: LGALS9 lectin, galactoside-binding, soluble, 9 (galectin 9).
4. Daley D, Mani VR, Mohan N, Akkad N, Ochi A, Heindel DW, Lee KB, Zambirinis CP, Pandian GS, Savadkar S, Torres-Hernandez A, Nayak S, Wang D, Hundeyin M, Diskin B, Aykut B, Werba G, Barilla RM, Rodriguez R, Chang S, Gardner L, Mahal LK, Ueberheide B, Miller G . 6 . Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance . Nature Medicine . 23 . 5 . 556–567 . May 2017 . 28394331 . 5419876 . 10.1038/nm.4314 .
5. Madireddi S, Eun SY, Lee SW, Nemčovičová I, Mehta AK, Zajonc DM, Nishi N, Niki T, Hirashima M, Croft M . Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies . The Journal of Experimental Medicine . 211 . 7 . 1433–48 . June 2014 . 24958847 . 4076583 . 10.1084/jem.20132687 .
6. Vaitaitis GM, Wagner DH . Galectin-9 controls CD40 signaling through a Tim-3 independent mechanism and redirects the cytokine profile of pathogenic T cells in autoimmunity . PLOS ONE . 7 . 6 . e38708 . 2012 . 22685601 . 3369903 . 10.1371/journal.pone.0038708 . 2012PLoSO...738708V . free .
7. Jia J, Abudu YP, Claude-Taupin A, Gu Y, Kumar S, Choi SW, Peters R, Mudd MH, Allers L, Salemi M, Phinney B, Johansen T, Deretic V . 6 . Galectins Control mTOR in Response to Endomembrane Damage . Molecular Cell . 70 . 1 . 120–135.e8 . April 2018 . 29625033 . 5911935 . 10.1016/j.molcel.2018.03.009 .
8. Jia J, Bissa B, Brecht L, Allers L, Choi SW, Gu Y, Zbinden M, Burge MR, Timmins G, Hallows K, Behrends C . 6 . January 2020 . AMPK, a Regulator of Metabolism and Autophagy, Is Activated by Lysosomal Damage via a Novel Galectin-Directed Ubiquitin Signal Transduction System . Molecular Cell . 77 . 5 . 951–969.e9. 10.1016/j.molcel.2019.12.028. 31995728 . 7785494 .
9. Werneburg NW, Guicciardi ME, Bronk SF, Kaufmann SH, Gores GJ . Tumor necrosis factor-related apoptosis-inducing ligand activates a lysosomal pathway of apoptosis that is regulated by Bcl-2 proteins . The Journal of Biological Chemistry . 282 . 39 . 28960–70 . September 2007 . 17686764 . 10.1074/jbc.M705671200 . free .
10. Taghiloo S, Allahmoradi E, Ebadi R, Tehrani M, Hosseini-Khah Z, Janbabaei G, Shekarriz R, Asgarian-Omran H . Upregulation of Galectin-9 and PD-L1 Immune Checkpoints Molecules in Patients with Chronic Lymphocytic Leukemia . Asian Pacific Journal of Cancer Prevention . 18 . 8 . 2269–2274 . August 2017 . 28843266 . 5697491 . 10.22034/APJCP.2017.18.8.2269 .
11. Asayama T, Tamura H, Ishibashi M, Kuribayashi-Hamada Y, Onodera-Kondo A, Okuyama N, Yamada A, Shimizu M, Moriya K, Takahashi H, Inokuchi K . Functional expression of Tim-3 on blasts and clinical impact of its ligand galectin-9 in myelodysplastic syndromes . Oncotarget . 8 . 51 . 88904–88917 . October 2017 . 29179486 . 5687656 . 10.18632/oncotarget.21492 .
12. Fujita . Koji . Iwama . Hisakazu . Oura . Kyoko . Tadokoro . Tomoko . Samukawa . Eri . Sakamoto . Teppei . Nomura . Takako . Tani . Joji . Yoneyama . Hirohito . Morishita . Asahiro . Himoto . Takashi . Hirashima . Mitsuomi . Masaki . Tsutomu . Cancer Therapy Due to Apoptosis: Galectin-9 . International Journal of Molecular Sciences . 1 January 2017 . 18 . 1 . 74 . 10.3390/ijms18010074. free . 28045432 . 5297709 .
13. Gonçalves Silva I, Yasinska IM, Sakhnevych SS, Fiedler W, Wellbrock J, Bardelli M, Varani L, Hussain R, Siligardi G, Ceccone G, Berger SM, Ushkaryov YA, Gibbs BF, Fasler-Kan E, Sumbayev VV . The Tim-3-galectin-9 Secretory Pathway is Involved in the Immune Escape of Human Acute Myeloid Leukemia Cells . eBioMedicine . 22 . 44–57 . August 2017 . 28750861 . 5552242 . 10.1016/j.ebiom.2017.07.018 .
14. Gao J, Qiu X, Li X, Fan H, Zhang F, Lv T, Song Y . Expression profiles and clinical value of plasma exosomal Tim-3 and Galectin-9 in non-small cell lung cancer . Biochemical and Biophysical Research Communications . 498 . 3 . 409–415 . February 2018 . 29452091 . 10.1016/j.bbrc.2018.02.114 .
15. Irie A, Yamauchi A, Kontani K, Kihara M, Liu D, Shirato Y, Seki M, Nishi N, Nakamura T, Yokomise H, Hirashima M . Galectin-9 as a prognostic factor with antimetastatic potential in breast cancer . Clinical Cancer Research . 11 . 8 . 2962–8 . April 2005 . 15837748 . 10.1158/1078-0432.CCR-04-0861 . 15041189 .
16. Zhang ZY, Dong JH, Chen YW, Wang XQ, Li CH, Wang J, Wang GQ, Li HL, Wang XD . Galectin-9 acts as a prognostic factor with antimetastatic potential in hepatocellular carcinoma . Asian Pacific Journal of Cancer Prevention . 13 . 6 . 2503–9 . 2012 . 22938412 . 10.7314/apjcp.2012.13.6.2503. free .
17. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC . Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity . The Journal of Experimental Medicine . 207 . 10 . 2187–94 . September 2010 . 20819927 . 2947065 . 10.1084/jem.20100643 .
18. Fu-Tong Liu . Liu FT . Regulatory roles of galectins in the immune response . International Archives of Allergy and Immunology . 136 . 4 . 385–400 . April 2005 . 15775687 . 10.1159/000084545 . 6614531 .