The deubiquitinase USP22 regulates PD-L1 degradation in human cancer cells
The deubiquitinase USP22 regulates PD-L1 degradation in human cancer cells
复制标题
去泛素酶 USP22 调节人类癌细胞中的 PD-L1 降解
DOI：
10.1186/s12964-020-00612-y
复制
发表时间：
2020-07-14
影响因子：
8.4
通讯作者：
Liu, Xiangguo
中科院分区：
文献类型：
--
作者：
Wang, Yu;Sun, Qingguo;Liu, Xiangguo
背景：许多癌症通过过度表达PD-L1来逃避免疫监视。PD-L1与其受体PD-1相互作用，导致T细胞增殖和活化减少，随后导致T淋巴细胞介导的癌细胞死亡。方法：以人非小细胞肺癌细胞和293FT细胞为研究对象，采用WB、免疫共沉淀、免疫荧光和流式细胞术等方法，研究USP 22对PD-L1和CSN 5的作用。以B16-F10细胞为研究对象，探讨USP 22对肿瘤发生的影响及T细胞的杀伤作用。结果：USP22与PD-L1相互作用，促进PD-L1的稳定性。USP 22使PD-L1去泛素化并抑制其蛋白酶体降解。此外，USP 22还与CSN 5相互作用，并通过去泛素化稳定CSN 5。USP22或CSN5均能促进PD-L1与另一种的相互作用。此外，USP 22去除了CSN 5和PD-L1的K6、K11、K27、K29、K33和K63连接的泛素链。此外，USP22耗竭抑制肿瘤发生并促进T细胞毒性。此外，USP22的表达与PD-L1在人非小细胞肺癌样本中的表达呈正相关。结论：在这里，我们建议USP22是PD-L1的一个新的调节因子。一方面，USP22可以通过去泛素化直接调节PD-L1的稳定性。另一方面，USP22通过USP22-CSN5-PD-L1轴调节PD-L1蛋白水平。此外，USP 22缺失可抑制肿瘤发生并促进T细胞细胞毒性。此外，在人非小细胞肺癌样本中，USP22表达与PD-L1表达呈正相关。总之，我们确定了PD-L1的新调节因子，并表征了USP22在PD-L1介导的免疫逃避中的重要作用。针对USP22可能是ICBT的新解决方案。
Background: Many cancers evade immune surveillance by overexpressing PD-L1. PD-L1 interacted with its receptor PD-1, resulting in reduction of T cell proliferation and activation and thereafter cancer cell death mediated by T-lymphocyte. Understanding the mechanisms that regulate PD-L1 was of vital importance for immune checkpoint blockade therapy (ICBT).Methods: Human non-small cell lung cancer cells and 293FT cells were used to investigate the function of USP22 upon PD-L1 and CSN5 by WB, Immunoprecipitation, Immunofluorescence and Flow cytometry analysis. B16-F10 cells were used to explore the role of USP22 on tumorigenesis and T cell cytotoxicity. The relationship between USP22 and PD-L1 expression was investigated by Immunohistochemistry analysis in human non-small cell lung cancer samples.Results: Our data showed that USP22 interacted with PD-L1 and promoted its stability. USP22 deubiquitinated PD-L1 and inhibited its proteasome degradation. Moreover, USP22 also interacted with CSN5 and stabilized CSN5 through deubiquitination. Either USP22 or CSN5 could facilitate the interaction of PD-L1 with the other one. Furthermore, USP22 removed K6, K11, K27, K29, K33 and K63-linked ubiquitin chain of both CSN5 and PD-L1. In addition, USP22 depletion inhibited tumorigenesis and promoted T cell cytotoxicity. Besides, USP22 expression positively correlated with PD-L1 expression in human non-small cell lung cancer samples.Conclusions: Here, we suggested that USP22 is a new regulator for PD-L1. On the one hand, USP22 could directly regulate PD-L1 stability through deubiquitination. On the other hand, USP22 regulated PD-L1 protein level through USP22-CSN5-PD-L1 axis. In addition, USP22 depletion inhibited tumorigenesis and promoted T cell cytotoxicity. Besides, USP22 expression positively correlated with PD-L1 expression in human non-small cell lung cancer samples. Together, we identified a new regulator of PD-L1 and characterized the important role of USP22 in PD-L1 mediated immune evasion. Targeting USP22 might be a new solution to ICBT.