Foot-and-mouth disease virus structural protein VP3 interacts with HDAC8 and promotes its autophagic degradation to facilitate viral replication

ABSTRACT

Macroautophagy/autophagy has been utilized by many viruses, including foot-and-mouth disease virus (FMDV), to facilitate replication, while the underlying mechanism of the interplay between autophagy and innate immune responses is still elusive. This study showed that HDAC8 (histone deacetylase 8) inhibits FMDV replication by regulating innate immune signal transduction and antiviral response. To counteract the HDAC8 effect, FMDV utilizes autophagy to promote HDAC8 degradation. Further data showed that FMDV structural protein VP3 promotes autophagy during virus infection and interacts with and degrades HDAC8 in an AKT-MTOR-ATG5-dependent autophagy pathway. Our data demonstrated that FMDV evolved a strategy to counteract host antiviral activity by autophagic degradation of a protein that regulates innate immune response during virus infection.

Abbreviations: 3-MA: 3-methyladenine; ATG: autophagy related; Baf-A1: bafilomycin A₁; CCL5: C-C motif chemokine ligand 5; Co-IP: co-immunoprecipitation; CQ: chloroquine phosphate; DAPI: 4”,6-diamidino-2-phenylindole; FMDV: foot-and-mouth disease virus; HDAC8: histone deacetylase 8; ISG: IFN-stimulated gene; IRF3: interferon regulatory factor 3; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; MAVS: mitochondria antiviral signaling protein; OAS: 2”−5’-oligoadenylate synthetase; RB1: RB transcriptional corepressor 1; SAHA: suberoylanilide hydroxamic acid; TBK1: TANK binding kinase 1; TCID₅₀: 50% tissue culture infectious doses; TNF/TNF-α: tumor necrosis factor; TSA: trichostatin A; UTR: untranslated region.

KEYWORDS:

• Autophagy
• FMDV
• histone deacetylase 8
• virus replication
• innate immune response

Acknowledgements

We thank Prof. Huichen Guo, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, for providing the FMDV (VP0, VP3, VP1) antibody. We thank the staff at the Instrument Center, Lanzhou Veterinary Research Institute, and Chinese Academy of Agricultural Science for advice and assistance in Confocal laser scanning microscopy sample observation and data collection.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2023.2233847

Additional information

Funding

This research was financially supported by the Agricultural Science and Technology Innovation Program of CAAS (CAAS-ASTIP-2021-LVRI), National Key R&D Program of China (2021YFD1800300) the Key Development and Research Foundation of Gansu (21YF5WA153), and the Natural Science Foundation Project of China (Grant no. 32202779).