Grass carp reovirus activates fish Ppp1r3g to suppress innate immunity and exacerbate hemorrhage via the 14-3-3ζ/Itgb3 signaling axis
- 1Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
- 2University of Chinese Academy of Sciences, Beijing, China
- 3Fisheries College, Hunan Agricultural University, Changsha, China
Abstract
Protein phosphatase 1 regulatory subunit 3G (PPP1R3G) is one of the regulatory subunits of protein phosphatase 1 (PP1). Current research on PPP1R3G is primarily focused on glycogen synthesis and lipid metabolism. However, the role of ppp1r3g in the innate immune response of fish has not been completely elucidated. This study demonstrated that ppp1r3g regulates RLR signaling pathway through interactions with Rig-I, Mda5, and Traf6. In parallel, Ppp1r3g inhibits platelet activation by regulating 14-3-3 zeta (14-3-3ζ) and consequently modulating the formation of the 14-3-3ζ-integrin-β3 (Itgb3) complex. In vivo analysis revealed that compared with the wild-type controls, ppp1r3g-null rare minnow (Gobiocypris rarus) and ppp1r3g-chimera grass carp (Ctenopharyngodon idella) exhibited significantly enhanced resistance to grass carp reovirus (GCRV), with markedly alleviated hemorrhagic symptoms post-infection. Furthermore, knockdown of ppp1r3g suppressed GCRV replication and upregulated type I interferon (IFN-1) expression in grass carp kidney (CIK) cells. Additionally, Ppp1r3g binds to the -ESKVFYLKMKGDYYRYL- fragment (EL17) of 14-3-3ζ via the Ser36/37 phosphorylation site located on the PP1c domain. This study also demonstrated that 14-3-3ζ interacts with Itgb3 through this fragment, indicating that Ppp1r3g competes with Itgb3 to bind 14-3-3ζ. Furthermore, Ppp1r3g dose-dependently promoted Itgb3 degradation via a proteolytic pathway. These findings indicate that Ppp1r3g negatively regulates innate antiviral immunity after GCRV stimulation and suppresses platelet and coagulation cascade activation by modulating the interaction between 14-3-3ζ and Itgb3 in fish. Author summary: Grass carp reovirus (GCRV) infection is associated with high lethality in grass carp and rare minnow. The primary symptom of GCRV is massive hemorrhaging in various tissues (hemorrhagic disease). Therefore, alleviating hemorrhagic symptoms is considered important for improving survival following GCRV infection. This study demonstrated that GCRV promotes ppp1r3g induction, suppressing the activation of the fish innate immune system by negatively regulating RLR signaling. Furthermore, Ppp1r3g competes with integrin-β3 (Itgb3) for binding to 14-3-3ζ and promotes Itgb3 degradation in a proteasome-dependent manner, which inhibits the formation of the 14-3-3ζ-Itgb3 complex, suppressing platelet activation. Thus, this study revealed the role of Ppp1r3g in fish innate immunity and elucidated its regulatory mechanism in the coagulation pathway.
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BibTeX
@article{wang2026grass,
title = {{Grass carp reovirus activates fish Ppp1r3g to suppress innate immunity and exacerbate hemorrhage via the 14-3-3ζ/Itgb3 signaling axis}},
author = {Ruyi Wang and Man Zhou and Yuxuan Wang and Xudong Hu and Han Zhang and Hong Cao},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014590},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014590},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Grass carp reovirus activates fish Ppp1r3g to suppress innate immunity and exacerbate hemorrhage via the 14-3-3ζ/Itgb3 signaling axis
AU - Ruyi Wang
AU - Man Zhou
AU - Yuxuan Wang
AU - Xudong Hu
AU - Han Zhang
AU - Hong Cao
PY - 2026
DA - 2026/09/18
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014590
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014590
AB - Protein phosphatase 1 regulatory subunit 3G (PPP1R3G) is one of the regulatory subunits of protein phosphatase 1 (PP1). Current research on PPP1R3G is primarily focused on glycogen synthesis and lipid metabolism. However, the role of ppp1r3g in the innate immune response of fish has not been completely elucidated. This study demonstrated that ppp1r3g regulates RLR signaling pathway through interactions with Rig-I, Mda5, and Traf6. In parallel, Ppp1r3g inhibits platelet activation by regulating 14-3-3 zeta (14-3-3ζ) and consequently modulating the formation of the 14-3-3ζ-integrin-β3 (Itgb3) complex. In vivo analysis revealed that compared with the wild-type controls, ppp1r3g-null rare minnow (Gobiocypris rarus) and ppp1r3g-chimera grass carp (Ctenopharyngodon idella) exhibited significantly enhanced resistance to grass carp reovirus (GCRV), with markedly alleviated hemorrhagic symptoms post-infection. Furthermore, knockdown of ppp1r3g suppressed GCRV replication and upregulated type I interferon (IFN-1) expression in grass carp kidney (CIK) cells. Additionally, Ppp1r3g binds to the -ESKVFYLKMKGDYYRYL- fragment (EL17) of 14-3-3ζ via the Ser36/37 phosphorylation site located on the PP1c domain. This study also demonstrated that 14-3-3ζ interacts with Itgb3 through this fragment, indicating that Ppp1r3g competes with Itgb3 to bind 14-3-3ζ. Furthermore, Ppp1r3g dose-dependently promoted Itgb3 degradation via a proteolytic pathway. These findings indicate that Ppp1r3g negatively regulates innate antiviral immunity after GCRV stimulation and suppresses platelet and coagulation cascade activation by modulating the interaction between 14-3-3ζ and Itgb3 in fish. Author summary: Grass carp reovirus (GCRV) infection is associated with high lethality in grass carp and rare minnow. The primary symptom of GCRV is massive hemorrhaging in various tissues (hemorrhagic disease). Therefore, alleviating hemorrhagic symptoms is considered important for improving survival following GCRV infection. This study demonstrated that GCRV promotes ppp1r3g induction, suppressing the activation of the fish innate immune system by negatively regulating RLR signaling. Furthermore, Ppp1r3g competes with integrin-β3 (Itgb3) for binding to 14-3-3ζ and promotes Itgb3 degradation in a proteasome-dependent manner, which inhibits the formation of the 14-3-3ζ-Itgb3 complex, suppressing platelet activation. Thus, this study revealed the role of Ppp1r3g in fish innate immunity and elucidated its regulatory mechanism in the coagulation pathway.
SN - 1553-7374
ER -