Biology:Galectin-9

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[3]

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 induced their proliferation inhibition and 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[8] 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.[8] 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.[7][8]

Clinical significance

The expression of galectin-9 has been detected on various hematological malignancies, such as CLL,[10] MDS,[11] Hodgkin and Non-Hodgkin 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][13] 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,[7][8] 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-diabetis drug metformin.[8]

References

  1. ↑ "Identification and characterization of galectin-9, a novel beta-galactoside-binding mammalian lectin". The Journal of Biological Chemistry 272 (9): 6078–86. February 1997. doi:10.1074/jbc.272.9.6078. PMID 9038233. 
  2. ↑ "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. doi:10.1074/jbc.272.10.6416. PMID 9045665. 
  3. ↑ 3.0 3.1 "Entrez Gene: LGALS9 lectin, galactoside-binding, soluble, 9 (galectin 9)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3965. 
  4. ↑ "Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance". Nature Medicine 23 (5): 556–567. May 2017. doi:10.1038/nm.4314. PMID 28394331. 
  5. ↑ "Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies". The Journal of Experimental Medicine 211 (7): 1433–48. June 2014. doi:10.1084/jem.20132687. PMID 24958847. 
  6. ↑ "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. doi:10.1371/journal.pone.0038708. PMID 22685601. Bibcode: 2012PLoSO...738708V. 
  7. ↑ 7.0 7.1 7.2 "Galectins Control mTOR in Response to Endomembrane Damage". Molecular Cell 70 (1): 120–135.e8. April 2018. doi:10.1016/j.molcel.2018.03.009. PMID 29625033. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 "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. January 2020. doi:10.1016/j.molcel.2019.12.028. PMID 31995728. 
  9. ↑ "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. doi:10.1074/jbc.M705671200. PMID 17686764. 
  10. ↑ "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. doi:10.22034/APJCP.2017.18.8.2269. PMID 28843266. 
  11. ↑ "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. doi:10.18632/oncotarget.21492. PMID 29179486. 
  12. ↑ "A modified version of galectin-9 induces cell cycle arrest and apoptosis of Burkitt and Hodgkin lymphoma cells". British Journal of Haematology 142 (4): 583–94. August 2008. doi:10.1111/j.1365-2141.2008.07229.x. PMID 18503581. 
  13. ↑ 13.0 13.1 "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. doi:10.1016/j.ebiom.2017.07.018. PMID 28750861. 
  14. ↑ "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. doi:10.1016/j.bbrc.2018.02.114. PMID 29452091. 
  15. ↑ "Galectin-9 as a prognostic factor with antimetastatic potential in breast cancer". Clinical Cancer Research 11 (8): 2962–8. April 2005. doi:10.1158/1078-0432.CCR-04-0861. PMID 15837748. 
  16. ↑ 16.0 16.1 "Galectin-9 acts as a prognostic factor with antimetastatic potential in hepatocellular carcinoma". Asian Pacific Journal of Cancer Prevention 13 (6): 2503–9. 2012. doi:10.7314/apjcp.2012.13.6.2503. PMID 22938412. 
  17. ↑ "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. doi:10.1084/jem.20100643. PMID 20819927. PMC 2947065. https://dash.harvard.edu/bitstream/handle/1/5265958/2947065.pdf?sequence=1. 
  18. ↑ "Regulatory roles of galectins in the immune response". International Archives of Allergy and Immunology 136 (4): 385–400. April 2005. doi:10.1159/000084545. PMID 15775687. 

Further reading

  • "Galectin-9 in physiological and pathological conditions". Glycoconjugate Journal 19 (7–9): 593–600. 2004. doi:10.1023/B:GLYC.0000014090.63206.2f. PMID 14758084. 
  • "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. January 1994. doi:10.1016/0378-1119(94)90802-8. PMID 8125298. 
  • "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. October 1997. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149. 
  • "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. doi:10.1074/jbc.273.27.16976. PMID 9642261. 
  • "Biological activities of ecalectin: a novel eosinophil-activating factor". Journal of Immunology 168 (4): 1961–7. February 2002. doi:10.4049/jimmunol.168.4.1961. PMID 11823532. 
  • "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. doi:10.1002/ijc.10436. PMID 12115481. 
  • "Interferon-gamma stimulates the expression of galectin-9 in cultured human endothelial cells". Journal of Leukocyte Biology 72 (3): 486–91. September 2002. PMID 12223516. 
  • "Selective eosinophil adhesion to fibroblast via IFN-gamma-induced galectin-9". Journal of Immunology 169 (10): 5912–8. November 2002. doi:10.4049/jimmunol.169.10.5912. PMID 12421975. 
  • "Galectin-9 induces apoptosis through the calcium-calpain-caspase-1 pathway". Journal of Immunology 170 (7): 3631–6. April 2003. doi:10.4049/jimmunol.170.7.3631. PMID 12646627. 
  • "Potential roles of galectins in myeloid differentiation into three different lineages". Journal of Leukocyte Biology 73 (5): 650–6. May 2003. doi:10.1189/jlb.0402163. PMID 12714580. 
  • "Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways". Oncogene 22 (21): 3307–18. May 2003. doi:10.1038/sj.onc.1206406. PMID 12761501. 
  • "Galectin-9 as a prognostic factor with antimetastatic potential in breast cancer". Clinical Cancer Research 11 (8): 2962–8. April 2005. doi:10.1158/1078-0432.CCR-04-0861. PMID 15837748. 
  • "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. doi:10.3892/ijmm.16.2.269. PMID 16012760. 
  • "Galectin-9 induces maturation of human monocyte-derived dendritic cells". Journal of Immunology 175 (5): 2974–81. September 2005. doi:10.4049/jimmunol.175.5.2974. PMID 16116184. 
  • "The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity". Nature Immunology 6 (12): 1245–52. December 2005. doi:10.1038/ni1271. PMID 16286920. 
  • "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. doi:10.1016/j.bbrc.2006.10.079. PMID 17069754. 

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