Galectin-9

Last updated

LGALS9
Protein LGALS9 PDB 2EAK.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases LGALS9 , HUAT, LGALS9A, galectin 9
External IDs OMIM: 601879; MGI: 109496; HomoloGene: 32078; GeneCards: LGALS9; OMA:LGALS9 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_002308
NM_009587
NM_001330163

NM_001159301
NM_010708

RefSeq (protein)

NP_001317092
NP_002299
NP_033665

NP_001152773
NP_034838

Location (UCSC) Chr 17: 27.63 – 27.65 Mb Chr 11: 78.85 – 78.88 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Galectin-9 was first isolated from mouse embryonic kidney in 1997 as a 36 kDa beta-galactoside lectin protein. [5] Human galectin-9 is encoded by the LGALS9 gene. [6] [7]

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. [7]

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, [8] CD137, [9] CD40 [10] ). For example, an interaction with CD40 on T-cells inhibits their proliferation and induces cell death. [10]

Galectin-9 also has important cytoplasmic, intracellular functions and controls AMPK [11] [12] 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. [13] Mild lysosomal damage, such as that caused by the anti-diabetes drug metformin [12] 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. [12] This signaling cascade directly links Galectin-9 intracellular function with ubiquitin 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. [11] [12]

Clinical significance

The expression of galectin-9 has been detected on various hematological malignancies, such as CLL, [14] MDS, [15] Hodgkin's lymphomas, [16] AML [17] or solid tumors, such as lung cancer, [18] breast cancer, [19] and hepatocellular carcinoma. [20]

HAVCR2/ galectin-9 interaction attenuated T-cell expansion and effectors function in tumor microenvironment and chronic infections. [21] [17] Moreover, galectin-9 contributed to tumorigenesis by tumor cell transformation, cell-cycle regulation, angiogenesis, and cell adhesion. [22] 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. [20] 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, [11] [12] 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. [12]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000168961 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000001123 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Wada J, Kanwar YS (February 1997). "Identification and characterization of galectin-9, a novel beta-galactoside-binding mammalian lectin". The Journal of Biological Chemistry. 272 (9): 6078–86. doi: 10.1074/jbc.272.9.6078 . PMID   9038233.
  6. Türeci O, Schmitt H, Fadle N, Pfreundschuh M, Sahin U (March 1997). "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. doi: 10.1074/jbc.272.10.6416 . PMID   9045665.
  7. 1 2 "Entrez Gene: LGALS9 lectin, galactoside-binding, soluble, 9 (galectin 9)".
  8. Daley D, Mani VR, Mohan N, Akkad N, Ochi A, Heindel DW, et al. (May 2017). "Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance". Nature Medicine. 23 (5): 556–567. doi:10.1038/nm.4314. PMC   5419876 . PMID   28394331.
  9. Madireddi S, Eun SY, Lee SW, Nemčovičová I, Mehta AK, Zajonc DM, Nishi N, Niki T, Hirashima M, Croft M (June 2014). "Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies". The Journal of Experimental Medicine. 211 (7): 1433–48. doi:10.1084/jem.20132687. PMC   4076583 . PMID   24958847.
  10. 1 2 Vaitaitis GM, Wagner DH (2012). "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. Bibcode:2012PLoSO...738708V. doi: 10.1371/journal.pone.0038708 . PMC   3369903 . PMID   22685601.
  11. 1 2 3 Jia J, Abudu YP, Claude-Taupin A, Gu Y, Kumar S, Choi SW, et al. (April 2018). "Galectins Control mTOR in Response to Endomembrane Damage". Molecular Cell. 70 (1): 120–135.e8. doi:10.1016/j.molcel.2018.03.009. PMC   5911935 . PMID   29625033.
  12. 1 2 3 4 5 6 Jia J, Bissa B, Brecht L, Allers L, Choi SW, Gu Y, et al. (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. doi:10.1016/j.molcel.2019.12.028. PMC   7785494 . PMID   31995728.
  13. Werneburg NW, Guicciardi ME, Bronk SF, Kaufmann SH, Gores GJ (September 2007). "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. doi: 10.1074/jbc.M705671200 . PMID   17686764.
  14. Taghiloo S, Allahmoradi E, Ebadi R, Tehrani M, Hosseini-Khah Z, Janbabaei G, Shekarriz R, Asgarian-Omran H (August 2017). "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. doi:10.22034/APJCP.2017.18.8.2269. PMC   5697491 . PMID   28843266.
  15. Asayama T, Tamura H, Ishibashi M, Kuribayashi-Hamada Y, Onodera-Kondo A, Okuyama N, Yamada A, Shimizu M, Moriya K, Takahashi H, Inokuchi K (October 2017). "Functional expression of Tim-3 on blasts and clinical impact of its ligand galectin-9 in myelodysplastic syndromes". Oncotarget. 8 (51): 88904–88917. doi:10.18632/oncotarget.21492. PMC   5687656 . PMID   29179486.
  16. Fujita K, Iwama H, Oura K, Tadokoro T, Samukawa E, Sakamoto T, Nomura T, Tani J, Yoneyama H, Morishita A, Himoto T, Hirashima M, Masaki T (1 January 2017). "Cancer Therapy Due to Apoptosis: Galectin-9". International Journal of Molecular Sciences. 18 (1): 74. doi: 10.3390/ijms18010074 . PMC   5297709 . PMID   28045432.
  17. 1 2 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 (August 2017). "The Tim-3-galectin-9 Secretory Pathway is Involved in the Immune Escape of Human Acute Myeloid Leukemia Cells". eBioMedicine. 22: 44–57. doi:10.1016/j.ebiom.2017.07.018. PMC   5552242 . PMID   28750861.
  18. Gao J, Qiu X, Li X, Fan H, Zhang F, Lv T, Song Y (February 2018). "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. doi:10.1016/j.bbrc.2018.02.114. PMID   29452091.
  19. Irie A, Yamauchi A, Kontani K, Kihara M, Liu D, Shirato Y, Seki M, Nishi N, Nakamura T, Yokomise H, Hirashima M (April 2005). "Galectin-9 as a prognostic factor with antimetastatic potential in breast cancer". Clinical Cancer Research. 11 (8): 2962–8. doi:10.1158/1078-0432.CCR-04-0861. PMID   15837748. S2CID   15041189.
  20. 1 2 Zhang ZY, Dong JH, Chen YW, Wang XQ, Li CH, Wang J, Wang GQ, Li HL, Wang XD (2012). "Galectin-9 acts as a prognostic factor with antimetastatic potential in hepatocellular carcinoma". Asian Pacific Journal of Cancer Prevention. 13 (6): 2503–9. doi: 10.7314/apjcp.2012.13.6.2503 . PMID   22938412.
  21. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC (September 2010). "Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity" (PDF). The Journal of Experimental Medicine. 207 (10): 2187–94. doi:10.1084/jem.20100643. PMC   2947065 . PMID   20819927.
  22. Liu FT (April 2005). "Regulatory roles of galectins in the immune response". International Archives of Allergy and Immunology. 136 (4): 385–400. doi:10.1159/000084545. PMID   15775687. S2CID   6614531.

Further reading