Department of Neurosurgery, The Second Affiliated Hospital of Chongqing, Medical University, 74 Linjiang Rd, Yuzhong, Chongqing, 400010, China.
Department of Health Medicine Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Cell Mol Life Sci. 2024 Oct 5;81(1):424. doi: 10.1007/s00018-024-05454-2.
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 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.
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.
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.
我们之前的研究发现，抑瘤因子氮渗透调节因子样 2（NPRL2）在神经胶质瘤中经常下调，导致恶性生长。然而，NPRL2 介导的肿瘤细胞与免疫细胞之间的串扰仍不清楚。
研究了 NPRL2 对三结构域蛋白 16（TRIM16）依赖性半胱氨酸蛋白酶依赖的 Galectin-3（Gal-3）泛素化降解的调控作用。研究了 Gal-3 对 CD8T 淋巴细胞（CD8T 细胞）铜摄取、免疫功能和铜死亡的影响。评估了 NPRL2 保护 CD8T 细胞免受 Gal-3 损伤的能力。此外，还分析了 NPRL2、TRIM16、Gal-3 和 CD8T 细胞在神经胶质瘤临床标本中的相关性。
NPRL2 通过失活 ERK1/2 增加了 TRIM16 的表达，从而促进了 Gal-3 的泛素化介导的降解，并减少了 Gal-3 从神经胶质瘤细胞中的释放。此外，Gal-3 加速了 CD8T 细胞的铜摄取，并引发了 CD8T 细胞的铜死亡，而 NPRL2 增加了 CD8T 细胞的募集，并防止了 Gal-3 对 CD8T 细胞的损伤。临床样本表明，NPRL2 表达与 TRIM16 表达呈正相关，与 Gal-3 表达呈负相关，而 Gal-3 表达与 CD8T 细胞聚集呈负相关。
神经胶质瘤衍生的 NPRL2/TRIM16/Gal-3 轴参与了 CD8T 细胞铜死亡的调节，为挽救 CD8T 细胞的免疫活性和逆转神经胶质瘤中的免疫抑制提供了一种有前途的策略。
