NPRL2 Promotes TRIM16-mediated Ubiquitination Degradation of Galectin-3 to Prevent CD8T Lymphocyte Cuproptosis in Glioma

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2024 Oct 5

PMID 39367988

Authors

Feng Wang

Jianhe Yue

Maoxin Zhang

Maoyuan Sun

Xu Luo

Hao Zhang

Yuanyuan Wu

Yuan Cheng

Jin Chen

Ning Huang

Affiliations

Soon will be listed here.

Abstract

Background: Our previous study found that tumor suppressor nitrogen permease regulator like-2(NPRL2) is frequently downregulated in glioma, leading to malignant growth. However, NPRL2-mediated crosstalk between tumor cells and immune cells remains unclear.

Methods: The regulatory effects of NPRL2 on tripartite motif-containing protein 16(TRIM16) dependent ubiquitination degradation of Galectin-3(Gal-3) were explored. The effects of Gal-3 on copper uptake, immunocompetence and cuproptosis were investigated in CD8T lymphocytes(CD8T cells). The ability of NPRL2 to protect CD8T cells from Gal-3 damage was evaluated. Furthermore, the correlations among NPRL2, TRIM16, Gal-3 and CD8T cell accumulation were analyzed in glioma clinical specimens.

Results: NPRL2 increased the TRIM16 expression via inactivation of ERK1/2, which in turn promoted the ubiquitination-mediated degradation of Gal-3 and diminished Gal-3 release from glioma cells. Moreover, Gal-3 accelerated copper uptake and triggered cuproptosis in CD8T cells, whereas NPRL2 increased CD8T cell recruitment and prevented impairment of CD8T cells by Gal-3. Clinical samples revealed that NPRL2 expression was positively associated with TRIM16 expression and negatively correlated with Gal-3, but Gal-3 expression was negatively associated with CD8T cell accumulation.

Conclusion: Glioma-derived NPRL2/TRIM16/Gal-3 axis participates in the regulation of CD8T cell cuproptosis, which provides a promising strategy to rescue the immune activity of CD8T cells and reverse immunosuppression in glioma.

References

Pastuszak-Lewandoska D, Kordiak J, Migdalska-Sek M, Czarnecka K, Antczak A, Gorski P . Quantitative analysis of mRNA expression levels and DNA methylation profiles of three neighboring genes: FUS1, NPRL2/G21 and RASSF1A in non-small cell lung cancer patients. Respir Res. 2015; 16:76. PMC: 4484633. DOI: 10.1186/s12931-015-0230-6. View

Wang L, Zhang X, Lin Z, Yang P, Xu H, Duan J . Tripartite motif 16 ameliorates nonalcoholic steatohepatitis by promoting the degradation of phospho-TAK1. Cell Metab. 2021; 33(7):1372-1388.e7. DOI: 10.1016/j.cmet.2021.05.019. View

Curti B, Koguchi Y, Leidner R, Rolig A, Sturgill E, Sun Z . Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor. J Immunother Cancer. 2021; 9(4). PMC: 8043038. DOI: 10.1136/jitc-2021-002371. View

Gordon-Alonso M, Hirsch T, Wildmann C, van der Bruggen P . Galectin-3 captures interferon-gamma in the tumor matrix reducing chemokine gradient production and T-cell tumor infiltration. Nat Commun. 2017; 8(1):793. PMC: 5630615. DOI: 10.1038/s41467-017-00925-6. View

Scafetta G, DAlessandria C, Bartolazzi A . Galectin-3 and cancer immunotherapy: a glycobiological rationale to overcome tumor immune escape. J Exp Clin Cancer Res. 2024; 43(1):41. PMC: 10845537. DOI: 10.1186/s13046-024-02968-2. View

Senft D, Qi J, Ronai Z . Ubiquitin ligases in oncogenic transformation and cancer therapy. Nat Rev Cancer. 2017; 18(2):69-88. PMC: 6054770. DOI: 10.1038/nrc.2017.105. View

Huang N, Cheng S, Mi X, Tian Q, Huang Q, Wang F . Downregulation of nitrogen permease regulator like-2 activates PDK1-AKT1 and contributes to the malignant growth of glioma cells. Mol Carcinog. 2015; 55(11):1613-1626. DOI: 10.1002/mc.22413. View

Kouo T, Huang L, Pucsek A, Cao M, Solt S, Armstrong T . Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells. Cancer Immunol Res. 2015; 3(4):412-23. PMC: 4390508. DOI: 10.1158/2326-6066.CIR-14-0150. View

Bausart M, Preat V, Malfanti A . Immunotherapy for glioblastoma: the promise of combination strategies. J Exp Clin Cancer Res. 2022; 41(1):35. PMC: 8787896. DOI: 10.1186/s13046-022-02251-2. View

10.

Xie J, Yang Y, Gao Y, He J . Cuproptosis: mechanisms and links with cancers. Mol Cancer. 2023; 22(1):46. PMC: 9990368. DOI: 10.1186/s12943-023-01732-y. View

11.

Pi Y, Feng Q, Sun F, Wang Z, Zhao Y, Chen D . Loss of SMURF2 expression enhances RACK1 stability and promotes ovarian cancer progression. Cell Death Differ. 2023; 30(11):2382-2392. PMC: 10657365. DOI: 10.1038/s41418-023-01226-w. View

12.

Wang Y, Tsai M, Chen Y, Hsieh P, Hung C, Lin H . NPRL2 down-regulation facilitates the growth of hepatocellular carcinoma via the mTOR pathway and autophagy suppression. Hepatol Commun. 2022; 6(12):3563-3577. PMC: 9701468. DOI: 10.1002/hep4.2019. View

13.

Giles J, Globig A, Kaech S, Wherry E . CD8 T cells in the cancer-immunity cycle. Immunity. 2023; 56(10):2231-2253. PMC: 11237652. DOI: 10.1016/j.immuni.2023.09.005. View

14.

Zhang I, Liu S, Zhang L, Liang R, Fang Q, Zhao J . RAGE ablation attenuates glioma progression and enhances tumor immune responses by suppressing galectin-3 expression. Neuro Oncol. 2022; 25(5):886-898. PMC: 10158202. DOI: 10.1093/neuonc/noac250. View

15.

Sampson C, Wang Q, Otkur W, Zhao H, Lu Y, Liu X . The roles of E3 ubiquitin ligases in cancer progression and targeted therapy. Clin Transl Med. 2023; 13(3):e1204. PMC: 9991012. DOI: 10.1002/ctm2.1204. View

16.

Stillman B, Hsu D, Pang M, Brewer C, Johnson P, Liu F . Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death. J Immunol. 2006; 176(2):778-89. DOI: 10.4049/jimmunol.176.2.778. View

17.

Wang X, Chen D, Shi Y, Luo J, Zhang Y, Yuan X . Copper and cuproptosis-related genes in hepatocellular carcinoma: therapeutic biomarkers targeting tumor immune microenvironment and immune checkpoints. Front Immunol. 2023; 14:1123231. PMC: 10157396. DOI: 10.3389/fimmu.2023.1123231. View

18.

Ran X, Zheng J, Chen L, Xia Z, Wang Y, Sun C . Single-Cell Transcriptomics Reveals the Heterogeneity of the Immune Landscape of IDH-Wild-Type High-Grade Gliomas. Cancer Immunol Res. 2023; 12(2):232-246. PMC: 10835213. DOI: 10.1158/2326-6066.CIR-23-0211. View

19.

Jackson C, Choi J, Lim M . Mechanisms of immunotherapy resistance: lessons from glioblastoma. Nat Immunol. 2019; 20(9):1100-1109. DOI: 10.1038/s41590-019-0433-y. View

20.

Peng Y, Dai H, Wang E, Lin C, Mo W, Peng G . TUSC4 functions as a tumor suppressor by regulating BRCA1 stability. Cancer Res. 2014; 75(2):378-86. PMC: 4804342. DOI: 10.1158/0008-5472.CAN-14-2315. View