PRKX down-regulates TAK1/IRF7 signaling in the antiviral innate immunity of black carp Mylopharyngodon piceus.
PRKX down-regulates TAK1/IRF7 signaling in the antiviral innate immunity of black carp Mylopharyngodon piceus.
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DOI：
10.3389/fimmu.2022.999219
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发表时间：
2022
影响因子：
7.3
通讯作者：
Feng, Hao
中科院分区：
文献类型：
--
作者：
Yang, Xiao;Ai, Yue;Chen, Liang;Wang, Chanyuan;Liu, Ji;Zhang, Jie;Li, Jun;Wu, Hui;Xiao, Jun;Chang, Mingxian;Feng, Hao
TGF-β激活的激酶1（TAK1）是与先天免疫密切相关的蛋白激酶，在人和哺乳动物中被X-连接蛋白激酶（PRKX）磷酸化激活，属于cAMP依赖性蛋白激酶家族。然而，在硬骨鱼中PRKX和TAK 1之间的关系仍然未知。本研究首次在脊椎动物中发现青鱼TAK1（bcTAK1）与bcIRF7相互作用，并上调bcIRF7介导的IFN信号转导。本研究探讨了青鱼PRKX同源物（bcPRKX）在bcTAK1/IFN信号转导中的作用。过表达bcPRKX抑制干扰素启动子的转录，但增强NF-κ B启动子的转录。转染bcPRKX基因的青鱼肾（MPK）细胞对鲤鱼春季病毒血症病毒（SVCV）具有较强的抗病毒活性，其中MX1、Viperin和PKR等抗病毒蛋白的mRNA表达水平明显升高。过表达的bcPRKX在荧光素酶报告基因测定和空斑测定中抑制了bcTAK1/bcIRF7/IFN信号传导。通过免疫荧光（IF）染色和免疫共沉淀（co-IP）分析鉴定了bcTAK1和bcPRKX之间的相互作用。此外，我们发现bcPRKX可以触发bcTAK1的降解。然而，溶酶体抑制剂氯喹，而不是蛋白酶体抑制剂MG-132，阻止bcPRKX介导的bcTAK1降解。因此，我们得出结论，bcPRKX抑制bcTAK1/bcIRF7/IFN信号转导过程中的天然免疫激活通过靶向bcTAK1和触发溶酶体依赖性降解的bcTAK1。
TGF-β-activated kinase-1 (TAK1), tightly related to innate immunity, is phosphorylated and activated by X-linked protein kinase (PRKX) in humans and mammals, which belongs to the c-AMP-dependent protein kinase family. However, the relationship between PRKX and TAK1 remains unknown in teleost. It has been reported in vertebrates for the first time that TAK1 of black carp (bcTAK1) interacts with bcIRF7 and is capable to up-regulate bcIRF7-mediated IFN signaling in our previous study. In this study, the role of PRKX homologue of black carp (Mylopharyngodon piceus) (bcPRKX) in bcTAK1/IFN signaling has been explored. Overexpression of bcPRKX suppressed the transcription of interferon promoters but enhanced the transcription of NF-κB promoter. Mylopharyngodon piceus kidney (MPK) cells transfected with shRNA targeting bcPRKX gene presented enhanced antiviral activity against spring viremia of carp virus (SVCV), in which the mRNA levels of the antiviral proteins were increased, including MX1, Viperin and PKR. Overexpressed bcPRKX dampened bcTAK1/bcIRF7/IFN signaling in the luciferase reporter assay and plaque assay. The interaction between bcTAK1 and bcPRKX has been identified by the immunofluorescence (IF) staining and co-immunoprecipitation (co-IP) assay. In addition, we found that bcPRKX can trigger the degradation of bcTAK1. However, the lysosome inhibitor chloroquine, but not the proteasome inhibitor MG-132, prevented the bcTAK1 degradation mediated by bcPRKX. Thus, we conclude that bcPRKX inhibits bcTAK1/bcIRF7/IFN signaling during the innate immune activation by targeting bcTAK1 and triggers lysosome-dependent degradation of bcTAK1.
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