Key Points
PPRV P protein inhibits type I IFN production.
PPRV P protein interacts with IRF3 to block the interaction between TBK1 and IRF3.
The 1–102 region of P protein is critical for the antagonistic function of P protein.
Visual Abstract
Abstract
Peste des petits ruminants virus (PPRV) is a Morbillivirus that causes highly contagious and severe disease in various ruminants. PPRV infection leads to a severe inhibition of host antiviral immune response. Our previous study demonstrated that PPRV V protein blocks IFN response by targeting STAT proteins. In the current study, we identified the phosphoprotein (P) as a novel antagonistic factor of PPRV to counteract host antiviral innate immune response. PPRV P protein significantly suppressed RIG-I–like receptor pathway signaling and impaired IFN-β and ISGs expression by targeting IFN regulatory factor (IRF)3 in both human embryonic kidney 293T cells and primary goat fibroblasts. The 1–102 region of P protein was critical for the antagonistic function of P protein. P protein interacted with IRF association domain (IAD) of IRF3 to block the interaction between TBK1 and IRF3. The interaction between TBK1 and the IAD of IRF3 is responsible for triggering the phosphorylation of IRF3. P protein competed with TBK1 to bind to the IAD of IRF3 that contributed to the decreased phosphorylation of IRF3, which, in turn, interfered with the dimerization of IRF3 and blocked IRF3 nuclear transportation. Besides, we also found that P protein interacted with IRF5 and IRF8. However, the involved mechanism remains unknown. Taken together, our results reveal a novel mechanism by which PPRV P protein antagonizes host antiviral innate immune response by interacting with the transcription factor IRF3, thereby inhibiting the type I IFN production and promoting viral replication.
Footnotes
This work was supported by grants from the National Key Research and Development Program of China (2016YFE0204100), the Key Technologies Research and Development Program of Gansu Province (19ZDNA001), the Key Development and Research Foundation of Yunnan (2018BB004), and the Chinese Academy of Agricultural Science and Technology Innovation Project (CAAS-ASTIP-2020-LVRI).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- CDV
- canine distemper virus
- coIP
- coimmunoprecipitation
- HA
- hemagglutinin
- HEK293T
- human embryonic kidney 293T cell line
- hpt
- hour posttransfection
- IAD
- IRF association domain
- IFA
- immunofluorescence assay
- IRF
- IFN regulatory factor
- ISG
- IFN-stimulated gene
- ISRE
- IFN-stimulated response element
- L
- polymerase
- M
- matrix
- MeV
- measles virus
- MOI
- multiplicity of infection
- N
- nucleocapsid
- NC siRNA
- negative control siRNA
- P
- phosphoprotein
- PAM
- pulmonary alveolar macrophage
- PPR
- peste des petits ruminants
- PPRV
- PPR virus
- qPCR
- real-time quantitative PCR
- RIG-I
- retinoic acid–inducible gene-I
- RLR
- RIG-I–like receptor
- RPV
- Rinderpest virus
- SeV
- Sendai virus
- siRNA
- small interfering RNA.
- Received April 21, 2020.
- Accepted November 15, 2020.
- Copyright © 2021 by The American Association of Immunologists, Inc.
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