TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models.
TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models.
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DOI：
10.1038/s41467-023-36523-y
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发表时间：
2023-02-16
影响因子：
16.6
通讯作者：
Liu, Na
中科院分区：
文献类型：
--
作者：
Li, Jun-Yan;Zhao, Yin;Gong, Sha;Wang, Miao-Miao;Liu, Xu;He, Qing-Mei;Li, Ying-Qin;Huang, Sheng-Yan;Qiao, Han;Tan, Xi-Rong;Ye, Ming-Liang;Zhu, Xun-Hua;He, Shi-Wei;Li, Qian;Liang, Ye-Lin;Chen, Kai-Lin;Huang, Sai-Wei;Li, Qing-Jie;Ma, Jun;Liu, Na
虽然放射治疗可以促进抗肿瘤免疫，但这种现象的机制尚不清楚。在这里，我们证明了肿瘤中E3泛素连接酶，肿瘤细胞固有的三方基元21 （TRIM21）的表达与鼻咽癌（NPC）对辐射和CD8+ T细胞介导的抗肿瘤免疫的反应呈负相关。敲除TRIM21可调节cGAS/STING胞质DNA传感通路，增强鼻咽癌细胞的抗原呈递能力，并激活辐射应答中细胞毒性T细胞介导的抗肿瘤免疫。在机制上，TRIM21通过k48连锁泛素化促进线粒体电压依赖性阴离子选择通道蛋白2 （VDAC2）的降解，从而抑制VDAC2寡聚物形成孔以释放线粒体DNA (mtDNA)，从而抑制辐射暴露后的i型干扰素反应。在鼻咽癌患者中，TRIM21高表达与预后差和放疗后肿瘤早期复发相关。我们的研究结果揭示了TRIM21在辐射诱导的抗肿瘤免疫中的关键作用，为提高鼻咽癌患者的放疗疗效提供了潜在的靶点。决定放射治疗反应的分子机制仍不完全清楚。在这里，作者证明E3泛素连接酶和细胞内Fc受体TRIM21在电离辐射后鼻咽癌肿瘤模型中损害CD8+ T细胞反应。
Although radiotherapy can promote antitumour immunity, the mechanisms underlying this phenomenon remain unclear. Here, we demonstrate that the expression of the E3 ubiquitin ligase, tumour cell-intrinsic tripartite motif-containing 21 (TRIM21) in tumours, is inversely associated with the response to radiation and CD8+ T cell-mediated antitumour immunity in nasopharyngeal carcinoma (NPC). Knockout of TRIM21 modulates the cGAS/STING cytosolic DNA sensing pathway, potentiates the antigen-presenting capacity of NPC cells, and activates cytotoxic T cell-mediated antitumour immunity in response to radiation. Mechanistically, TRIM21 promotes the degradation of the mitochondrial voltage-dependent anion-selective channel protein 2 (VDAC2) via K48-linked ubiquitination, which inhibits pore formation by VDAC2 oligomers for mitochondrial DNA (mtDNA) release, thereby inhibiting type-I interferon responses following radiation exposure. In patients with NPC, high TRIM21 expression was associated with poor prognosis and early tumour relapse after radiotherapy. Our findings reveal a critical role of TRIM21 in radiation-induced antitumour immunity, providing potential targets for improving the efficacy of radiotherapy in patients with NPC. The molecular mechanisms determining the response to radiotherapy remain incompletely understood. Here, the authors demonstrate that the E3 ubiquitin ligase and intracellular Fc receptor, TRIM21, impairs CD8+ T cell responses in nasopharyngeal carcinoma tumour models following ionizing radiation.
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影响因子：
6.2
作者：
Delaney, G;Jacob, S;Barton, M
通讯作者：
Barton, M
影响因子：
30.5
作者：
Han, Chuanhui;Liu, Zhida;Fu, Yang-Xin
通讯作者：
Fu, Yang-Xin
影响因子：
56.9
作者：
Cheng, EHY;Sheiko, TV;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
8.4
作者：
Boulle, G.;Velut, Y.;Damotte, D.
通讯作者：
Damotte, D.
DOI：
10.4049/jimmunol.181.3.1780
发表时间：
2008-08-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Higgs R;Ní Gabhann J;Ben Larbi N;Breen EP;Fitzgerald KA;Jefferies CA
通讯作者：
Jefferies CA