Role of BCLAF-1 in PD-L1 stabilization in response to ionizing irradiation.
Role of BCLAF-1 in PD-L1 stabilization in response to ionizing irradiation.
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BCLAF-1在PD-L1对电离辐射的稳定反应中的作用
DOI：
10.1111/cas.15056
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发表时间：
2021-10
期刊：
影响因子：
5.7
通讯作者：
Xu B
中科院分区：
文献类型：
--
作者：
Ma Z;Wang H;Meng F;Han Y;Chen Y;Xiao M;Jiang H;Yu Z;Xu B
程序性细胞死亡配体1（PD-L1）是一种主要的免疫抑制检查点蛋白，由肿瘤细胞表达，以破坏抗癌免疫。最近的研究表明，电离辐射（IR）上调肿瘤细胞中PD-L1的表达。然而，IR诱导的DNA损伤反应（DDR）是否直接调节PD-L1表达及其上调的功能意义尚未完全了解。在这里，我们表明IR诱导的PD-L1表达上调通过转录和翻译后机制进行。上调的PD-L1主要存在于细胞膜上，导致共培养系统中的T细胞凋亡。使用质谱法，我们鉴定了PD-L1相互作用蛋白，并发现BCLAF 1（Bcl 2相关转录因子1）是PD-L1响应IR的重要调节因子。BCLAF 1缺失通过促进PD-L1的泛素化来降低PD-L1表达。此外，我们发现CMTM 6在IR反应中上调，并参与BCLAF 1依赖性PD-L1上调。最后，我们证明了ATM/BCLAF 1/PD-L1轴调节PD-L1对IR的稳定性。总之，我们的研究结果揭示了DDR中PD-L1表达的一种新的调节机制。IR诱导的PD-L1表达上调通过翻译后机制进行。我们将BCLAF 1确定为响应IR的新PD-L1稳定调节剂。
Programmed cell death ligand 1 (PD‐L1) is a major immunosuppressive checkpoint protein expressed by tumor cells to subvert anticancer immunity. Recent studies have shown that ionizing radiation (IR) upregulates the expression of PD‐L1 in tumor cells. However, whether an IR‐induced DNA damage response (DDR) directly regulates PD‐L1 expression and the functional significance of its upregulation are not fully understood. Here, we show that IR‐induced upregulation of PD‐L1 expression proceeds through both transcriptional and post‐translational mechanisms. Upregulated PD‐L1 was predominantly present on the cell membrane, resulting in T‐cell apoptosis in a co‐culture system. Using mass spectrometry, we identified PD‐L1 interacting proteins and found that BCLAF1 (Bcl2 associated transcription factor 1) is an important regulator of PD‐L1 in response to IR. BCLAF1 depletion decreased PD‐L1 expression by promoting the ubiquitination of PD‐L1. In addition, we show that CMTM6 is upregulated in response to IR and participates in BCLAF1‐dependent PD‐L1 upregulation. Finally, we demonstrated that the ATM/BCLAF1/PD‐L1 axis regulated PD‐L1 stabilization in response to IR. Together, our findings reveal a novel regulatory mechanism of PD‐L1 expression in the DDR. IR‐induced PD‐L1 upregulation expression proceeded through post‐translational mechanisms. We identified BCLAF1 as a new PD‐L1 stabilization regulator in response to IR.
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