Foot-and-mouth disease virus structural protein VP3 degrades Janus kinase 1 to inhibit IFN-γ signal transduction pathways

ABSTRACT

Foot-and-mouth disease is a highly contagious viral disease of cloven-hoofed animals that is caused by foot-and-mouth disease virus (FMDV). To replicate efficiently in vivo, FMDV has evolved methods to circumvent host antiviral defense mechanisms, including those induced by interferons (IFNs). Previous research has focused on the effect of FMDV L^pro and 3C^pro on type I IFNs. In this study, FMDV VP3 was found to inhibit type II IFN signaling pathways. The overexpression of FMDV VP3 inhibited the IFN-γ-triggered phosphorylation of STAT1 at Tyr701 and the subsequent expression of downstream genes. Mechanistically, FMDV VP3 interacted with JAK1/2 and inhibited the tyrosine phosphorylation, dimerization and nuclear accumulation of STAT1. FMDV VP3 also disrupted the assembly of the JAK1 complex and degraded JAK1 but not JAK2 via a lysosomal pathway. Taken together, the results reveal a novel mechanism used by which FMDV VP3 counteracts the type II IFN signaling pathways.

KEYWORDS:

• Foot-and-mouth disease virus
• IFN-γ
• signaling pathway
• janus kinase 1
• structural protein VP3

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank other members of Shu's laboratory for stimulating discussion and technical help.

Funding

This work was supported by the following funding sources: the National Natural Science Foundation of China (Nos. 31402179, 31302118, 31402179, U1501213), the National Science & Technology Support Plan Program (No.2015BAD12B04), the Gansu Science Foundation for Distinguished Young Scholars (No. 145RJDA328), the Key Technologies R&D Program of Gansu Province (No. 1302NKDA027) and the Ministry of agriculture 948 project (2015-Z6). The funding bodies had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.