Cyclin-dependent kinase 5 negatively regulates antiviral immune response by disrupting myeloid differentiation primary response protein 88 self-association

ABSTRACT

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 vesicular stomatitis virus (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.

KEYWORDS:

• CDK5
• IFNs
• INNATE IMMUNITY
• MyD88

Acknowledgements

We thank professor Qinmiao Sun (Institute of Zoology, Chinese Academy of Sciences) for kindly providing the VSV-GFP virus. We are grateful to Paul Chu, Guest Professor of the Institute of Microbiology, Chinese Academy of Sciences, for his help during the preparation of the manuscript. The authors would like to express their gratitude to EditSprings (https://www.editsprings.cn) for the expert linguistic services provided.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

J.R. and J.W. discovered that CDK5 can negatively regulate the production of IFNs and participated in most experiments. H.C. supplied and propagated all the virus used in this paper. J. R. designed and carried out all the quantitative real-time PCR. Y.W cultured all the cells used in this paper. L.G., D.J. and X.L. constructed all the plasmids used in this paper. T.T. supervised the project. J.R., J.W. and T.T. wrote the manuscript with input from all authors.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materialshttps://doi.org/10.6084/m9.figshare.23512494.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21505594.2023.2223394.

Additional information

Funding

This work was supported by National Natural Science Foundation of China (82030033, 92254301, 81921006, 32070780), and the State Key Laboratory of Membrane Biology.