Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China; Shanghai Key Laboratory of Veterinary Biotechnology, Shanghai, People's Republic of China.
Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.
Virus Res. 2023 Mar;326:199065. doi: 10.1016/j.virusres.2023.199065. Epub 2023 Feb 8.
The receptor tyrosine kinases TYRO3, AXL, and MERTK (TAM) are transmembrane proteins associated with the regulation of the innate immune response. In this study, the role of the chicken-derived MERTK protein (chMertk) in the regulation of the type I interferon (IFN) signaling pathway and its antiviral effect were investigated in vitro. Newcastle disease (ND) caused by the Newcastle disease virus (NDV) is able to widely spread in chickens and give rise to massive losses in the poultry industry around the world. We found that the overexpression of the exogenous chMertk upregulated the STAT1 phosphorylation and the expression of IFN-stimulated gene IFITM3 and significantly reduced the NDV titer (p < 0.05). A mutation assay showed that three tyrosine residues (Y739, Y743, and Y744) in chMertk promoted STAT1 phosphorylation and inhibited NDV replication. However, the chicken-derived E3 ubiquitin ligase CBL significantly negatively regulated chMertk expression, thus attenuating STAT1 phosphorylation. chMertk function was restored by the ubiquitin-proteasome inhibitor MG132, demonstrating that chMertk was controlled by Casitas B-lineage proto-oncogene (CBL) ubiquitination and degradation. Together, these results suggested that chMertk participated in regulating the immune responses to NDV infection, and that CBL significantly downregulated the expression of chMertk through its ubiquitination and degradation, to maintain cellular homeostasis. Overall, our study provided new insights into the role of chMertk in regulating the innate immune response and its anti-NDV activity.
受体酪氨酸激酶 TYRO3、AXL 和 MERTK（TAM）是与先天免疫反应调节相关的跨膜蛋白。在这项研究中，研究了鸡源性 MERTK 蛋白（chMertk）在调节 I 型干扰素（IFN）信号通路及其抗病毒作用中的作用。由新城疫病毒（NDV）引起的新城疫（ND）能够在鸡中广泛传播，并在全球家禽业造成巨大损失。我们发现，外源性 chMertk 的过表达上调了 STAT1 磷酸化和 IFN 刺激基因 IFITM3 的表达，并显著降低了 NDV 滴度（p < 0.05）。突变试验表明，chMertk 中的三个酪氨酸残基（Y739、Y743 和 Y744）促进了 STAT1 磷酸化并抑制了 NDV 复制。然而，鸡源性 E3 泛素连接酶 CBL 显著负调控 chMertk 的表达，从而减弱了 STAT1 磷酸化。泛素蛋白酶体抑制剂 MG132 恢复了 chMertk 的功能，表明 chMertk 受 Casitas B 细胞系原癌基因（CBL）泛素化和降解的调控。总之，这些结果表明 chMertk 参与调节对 NDV 感染的免疫反应，CBL 通过其泛素化和降解显著下调 chMertk 的表达，以维持细胞内稳态。总的来说，我们的研究提供了 chMertk 在调节先天免疫反应及其抗 NDV 活性中的作用的新见解。
