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GETV nsP2 plays a critical role in the interferon antagonism and viral pathogenesis.

ABSTRACT: Getah virus (GETV) was becoming more serious and posing a potential threat to animal safety and public health. Currently, there is limited comprehension regarding the pathogenesis and immune evasion mechanisms employed by GETV. Our study reveals that GETV infection exhibits the capacity for interferon antagonism. Specifically, the nonstructural protein nsP2 of GETV plays a crucial role in evading the host immune response. GETV nsP2 effectively inhibits the induction of IFN-β by blocking the phosphorylation and nuclear translocation of IRF3. Additionally, GETV nsP2 hinders the phosphorylation of STAT1 and its nuclear accumulation, leading to significantly impaired JAK-STAT signaling. Furthermore, the amino acids K648 and R649, situated in the C-terminal region of GETV nsP2, play a crucial role in facilitating nuclear localization. Not only do they affect the interference of nsP2 with the innate immune response, but they also exert an influence on the pathogenicity of GETV in mice. In summary, our study reveals novel mechanisms by which GETV evades the immune system, thereby offering a foundation for comprehending the pathogenic nature of GETV. Video Abstract.

SUBMITTER: Mou C

PROVIDER: S-EPMC10729338 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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GETV nsP2 plays a critical role in the interferon antagonism and viral pathogenesis.

Mou Chunxiao C Meng Hui H Shi Kaichuang K Huang Yanmei Y Liu Meiqi M Chen Zhenhai Z

Cell communication and signaling : CCS 20231218 1

Getah virus (GETV) was becoming more serious and posing a potential threat to animal safety and public health. Currently, there is limited comprehension regarding the pathogenesis and immune evasion mechanisms employed by GETV. Our study reveals that GETV infection exhibits the capacity for interferon antagonism. Specifically, the nonstructural protein nsP2 of GETV plays a crucial role in evading the host immune response. GETV nsP2 effectively inhibits the induction of IFN-β by blocking the phos ...[more]

PMID: 38110975

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Project description:Autophagy-related protein 7 (ATG7) is an essential autophagy effector enzyme. Although it is well known that autophagy plays crucial roles in the infections with various viruses including influenza A virus (IAV), function and underlying mechanism of ATG7 in infection and pathogenesis of IAV remain poorly understood. Here, in vitro studies showed that ATG7 had profound effects on replication of IAV. Depletion of ATG7 markedly attenuated the replication of IAV, whereas overexpression of ATG7 facilitated the viral replication. ATG7 conditional knockout mice were further employed and exhibited significantly resistant to viral infections, as evidenced by a lower degree of tissue injury, slower body weight loss, and better survival, than the wild type animals challenged with either IAV (RNA virus) or pseudorabies virus (DNA virus). Interestingly, we found that ATG7 promoted the replication of IAV in autophagy-dependent and -independent manners, as inhibition of autophagy failed to completely block the upregulation of IAV replication by ATG7. To determine the autophagy-independent mechanism, transcriptome analysis was utilized and demonstrated that ATG7 restrained the production of interferons (IFNs). Loss of ATG7 obviously enhanced the expression of type I and III IFNs in ATG7-depleted cells and mice, whereas overexpression of ATG7 impaired the interferon response to IAV infection. Consistently, our experiments demonstrated that ATG7 significantly suppressed IRF3 activation during the IAV infection. Furthermore, we identified long noncoding RNA (lncRNA) GAPLINC as a critical regulator involved in the promotion of IAV replication by ATG7. Importantly, both inactivation of IRF3 and inhibition of IFN response caused by ATG7 were mediated through control over GAPLINC expression, suggesting that GAPLINC contributes to the suppression of antiviral immunity by ATG7. Together, these results uncover an autophagy-independent mechanism by which ATG7 suppresses host innate immunity and establish a critical role for ATG7/GAPLINC/IRF3 axis in regulating IAV infection and pathogenesis.

Dataset Information

GETV nsP2 plays a critical role in the interferon antagonism and viral pathogenesis.

Publications

GETV nsP2 plays a critical role in the interferon antagonism and viral pathogenesis.

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