TRIM22 negatively regulates MHC-II expression
TRIM22 negatively regulates MHC-II expression
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TRIM22 负向调节 MHC-II 表达
DOI：
10.1016/j.bbamcr.2022.119318
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Hatakeyama Shigetsugu
中科院分区：
文献类型：
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作者：
Inoue Ayano;Watanabe Masashi;Kondo Takeshi;Hirano Satoshi;Hatakeyama Shigetsugu
近年来，癌症治疗的发展取得了显著的突破，检查点阻断免疫疗法受到了广泛的关注。为了提高检查点阻断免疫疗法的治疗效果，最近的研究揭示了通过增加癌细胞中主要组织相容性复合体（MHC） II类分子来激活CD4+T细胞的重要性。在这里，我们证明了tripartite motifi -containing (TRIM) 22负性调节MHC-II的表达。使用Cas9-sgRNAs敲除TRIM22基因导致MHC-II蛋白增加，而TRIM22过表达显著降低MHC-II蛋白。在MHC-II转录调控中起重要作用的MHC-II和II类反激活子（CIITA） mRNA水平不受TRIM22的影响。此外，敲除TRIM22并没有抑制MHC-II蛋白的降解，而是促进了MHC-II蛋白的降解。这些结果表明，TRIM22通过转录或降解以外的多种机制降低MHC-II蛋白水平。我们发现，抑制TRIM22可以增加癌细胞中MHC-II的表达量，这可能为潜在的治疗靶点提供生物学基础，从而增强检查点阻断免疫疗法。
The development of cancer treatment has recently achieved a remarkable breakthrough, and checkpoint blockade immunotherapy has received much attention. To enhance the therapeutic efficacy of checkpoint blockade immunotherapy, recent studies have revealed the importance of activation of CD4+T cells via an increase in major histocompatibility complex (MHC) class II molecules in cancer cells. Here, we demonstrate that tripartite motif-containing (TRIM) 22, negatively regulates MHC-II expression. Gene knockout of TRIM22 using Cas9-sgRNAs led to an increase of MHC-II proteins, while TRIM22 overexpression remarkably decreased MHC-II proteins. mRNA levels of MHC-II and class II transactivator (CIITA), which plays an essential role in the regulation of MHC-II transcription, were not affected by TRIM22. Furthermore, TRIM22 knockout did not suppress the degradation of MHC-II protein but rather promoted it. These results suggest that TRIM22 decreases MHC-II protein levels through a combination of multiple mechanisms other than transcription or degradation. We showed that inhibition of TRIM22 can increase the amount of MHC-II expression in cancer cells, suggesting a possibility of providing the biological basis for a possible therapeutic target to potentiate checkpoint blockade immunotherapy.