NPRL2 promotes TRIM16-mediated ubiquitination degradation of Galectin-3 to prevent CD8+T lymphocyte cuproptosis in glioma

作者：Feng Wang, Jianhe Yue, Maoxin Zhang, Maoyuan Sun, Xu Luo, Hao Zhang, Yuanyuan Wu, Yuan Cheng, Chen Jin, Ning Huang · 发表于：Cellular and Molecular Life Sciences · 年份：2024 · DOI：10.1007/s00018-024-05454-2 · 被引用次数：8 · 研究领域：Galectins and Cancer Biology、Signaling Pathways in Disease、Immune Cell Function and Interaction

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. 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 CD8 + T lymphocytes(CD8 + T cells). The ability of NPRL2 to protect CD8 + T cells from Gal-3 damage was evaluated. Furthermore, the correlations among NPRL2, TRIM16, Gal-3 and CD8 + T cell accumulation were analyzed in glioma clinical specimens. 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 CD8 + T cells, whereas NPRL2 increased CD8 + T cell recruitment and prevented impairment of CD8 + T 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 CD8 + T cell accumulation. Glioma-derived NPRL2/TRIM16/Gal-3 axis participates in the regulation of CD8 + T cell cuproptosis, which provides a promising strategy to rescue the immune activity of CD8 + ...