State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Virulence. 2023 Dec;14(1):2223394. doi: 10.1080/21505594.2023.2223394.
As a member of the pattern recognition receptors (PRRs) involving in the innate immune system, Toll-like receptors (TLRs) can sense a wide range of microbial pathogens and combat infections by producing antimicrobial products, inflammatory cytokines, and chemokines. All TLRs, with the exception of TLR3, activate a signalling cascade via the myeloid differentiation primary response gene 88 (MyD88). Therefore, the activation of MyD88-dependent signalling pathway must be finely controlled. Herein, we identified that cyclin-dependent kinase 5 (CDK5) negatively regulated TLR-MyD88 signalling pathway by targeting MyD88. Overexpression of CDK5 reduced the production of interferons (IFNs), while a deficiency in CDK5 increased the expression of IFNs in response to (VSV) infection. Mechanistically, CDK5 suppressed the formation of MyD88 homodimers, resulting in the attenuated production of IFNs induced by VSV infection. Surprisingly, its kinase activity does not play a role in this process. Therefore, CDK5 can act as an internal regulator to prevent excessive production of IFNs by restricting TLR-MyD88-induced activation of antiviral innate immunity in A549 cells.
作为参与固有免疫系统的模式识别受体（PRRs）的成员，Toll 样受体（TLRs）可以通过产生抗菌产品、炎症细胞因子和趋化因子来感知广泛的微生物病原体并对抗感染。除 TLR3 外，所有 TLR 都通过髓样分化初级反应基因 88（MyD88）激活信号级联反应。因此，必须精细控制 MyD88 依赖性信号通路的激活。在此，我们发现细胞周期蛋白依赖性激酶 5（CDK5）通过靶向 MyD88 负调控 TLR-MyD88 信号通路。CDK5 的过表达减少了干扰素（IFNs）的产生，而 CDK5 的缺乏则增加了对（VSV）感染的 IFN 表达。在机制上，CDK5 抑制了 MyD88 同源二聚体的形成，导致 VSV 感染诱导的 IFN 产生减弱。令人惊讶的是，其激酶活性在这个过程中不起作用。因此，CDK5 可以作为一种内部调节剂，通过限制 TLR-MyD88 诱导的抗病毒固有免疫的激活，防止 IFN 的过度产生，从而在 A549 细胞中发挥作用。
