2AB protein of Senecavirus A antagonizes selective autophagy and type I interferon production by degrading LC3 and MARCHF8

Sun, Dage; Kong, Ning; Dong, Sujie; Chen, Xiaoyong; Qin, Wenzhen; Wang, Hua; Jiao, Yajuan; Zhai, Huanjie; Li, Liwei; Gao, Fei; Yu, Lingxue; Zheng, Hao; Wu, Tong; Yu, Hai; Zhang, Wen; Tong, Guangzhi; Shan, Tongling

doi:10.1080/15548627.2021.2015740

Cited by 32 publications

(17 citation statements)

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“…It likely enhances membrane permeability, acting like a viroporin (4). Furthermore, SVA 2AB protein promoted MARCHF8 and MAVS degradation to inhibit IFN-I signaling during SVA infection (35). In contrast, the 3C protein of SVA cleaves PABPC1 to promote viral replication through 3C protease activity (36) and 3C protein-induced hnRNP A1 degradation through its protease activity to promote virus replication (37).…”

Section: Discussionmentioning

confidence: 99%

2B and 3C Proteins of Senecavirus A Antagonize the Antiviral Activity of DDX21 via the Caspase-Dependent Degradation of DDX21

et al. 2022

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Senecavirus A (SVA), also known as Seneca Valley virus, is a recently discovered picornavirus that can cause swine vesicular disease, posing a great threat to the global swine industry. It can replicate efficiently in cells, but the molecular mechanism remains poorly understood. This study determined the host’s differentially expressed proteins (DEPs) during SVA infection using dimethyl labeling based on quantitative proteomics. Among the DE proteins, DDX21, a member of the DEAD (Asp-Glu-Ala-Asp)-box RNA helicase (DDX) family, was downregulated and demonstrated inhibiting SVA replication by overexpression and knockdown experiment. To antagonize this antiviral effect of DDX21, SVA infection induces the degradation of DDX21 by 2B and 3C proteins. The Co-IP results showed that 2B and 3C did not interact with DDX21, suggesting that the degradation of DDX21 did not depend on their interaction. Moreover, the 3C protein protease activity was necessary for the degradation of DDX21. Furthermore, our study revealed that the degradation of DDX21 by 2B and 3C proteins of SVA was achieved through the caspase pathway. These findings suggest that DDX21 was an effective antiviral factor for suppressing SVA infection and that SVA antagonized its antiviral effect by degrading DDX21, which will be useful to guide further studies into the mechanism of mutual regulation between SVA and the host.

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Section: Discussionmentioning

confidence: 99%

2B and 3C Proteins of Senecavirus A Antagonize the Antiviral Activity of DDX21 via the Caspase-Dependent Degradation of DDX21

et al. 2022

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“…As a newly emerging causative agent for pigs, exploring the pathogenic and immune escape mechanisms of SVA from diverse aspects will be conducive to finding potential antiviral targets or strategies. To date, a number of studies have demonstrated that there exist extremely complex interactions between SVA and autophagy/apoptosis in host cells [ 34 , 35 ]. For example, Sun and colleagues showed that SVA infection can induce autophagy in the early stage of SVA infection, which functions to inhibit SVA replication by degrading the SVA 3C protein; however, in the late stage of infection, SVA utilizes 2AB protein to inhibit autophagy via interaction with MARCHF8/MARCH8 and LC3 to facilitate viral replication [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…To date, a number of studies have demonstrated that there exist extremely complex interactions between SVA and autophagy/apoptosis in host cells [ 34 , 35 ]. For example, Sun and colleagues showed that SVA infection can induce autophagy in the early stage of SVA infection, which functions to inhibit SVA replication by degrading the SVA 3C protein; however, in the late stage of infection, SVA utilizes 2AB protein to inhibit autophagy via interaction with MARCHF8/MARCH8 and LC3 to facilitate viral replication [ 34 ]. Wen et al (2021) found that, although selective autophagy receptor SQSTM1/p62 functions to inhibit SVA replication by targeting viral VP1 and VP3 to phagophores for an autophagic degradation, SVA has evolved an antagonistic mechanism against the function of selective autophagic degradation via cleavage of SQSTM1/p62 at glutamic acid 355, glutamine 392, and glutamine 395 by the SVA 3C protease (3C pro ) [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative Proteomic Analysis Reveals Mx1 Inhibits Senecavirus A Replication in PK-15 Cells by Interacting with the Capsid Proteins VP1, VP2 and VP3

Gao

Zhang

et al. 2022

Viruses

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As an emergent picornavirus pathogenic to pigs, Senecavirus A (SVA) can replicate in pig kidneys and proliferates well in porcine kidney epithelial PK-15 cells. Here, tandem mass tags (TMT) labeling coupled with liquid chromatography–tandem mass spectrometry (LC-MS/MS) was used to analyze the proteome dynamic changes in PK-15 cells during SVA infection. In total, 314, 697 and 426 upregulated differentially expressed proteins (DEPs) and 131, 263 and 342 downregulated DEPs were identified at 12, 24 and 36 hpi, respectively. After ensuring reliability of the proteomic data by quantitative PCR and Western blot testing of five randomly selected DEPs, Mx1, eIF4E, G6PD, TOP1 and PGAM1, all the DEPs were subjected to multiple bioinformatics analyses, including GO, COG, KEGG and STRING. The results reveal that the DEPs were mainly involved in host innate and adaptive immune responses in the early and middle stages of SVA infection, while the DEPs mainly participated in various metabolic processes in the late stage of infection. Finally, we demonstrated that Mx1 protein exerts antiviral activity against SVA by interacting with VP1 and VP2 proteins dependent on its GTPase, oligomerization and interaction activities, while Mx1 interacts with VP3 only depending on its oligomerization activity. Collectively, our study provides valuable clues for further investigation of SVA pathogenesis.

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“…HIV Nef is reported to reduce autophagic maturation by targeting Beclin-1, thus restricting autophagic processing of HIV ( Kyei et al, 2009 ). 2AB protein of Seneca virus A (SVA) is reported to antagonize selective autophagy process by degrading LC3 and inhibit autophagic degradation of viral 3C protein ( Sun et al, 2021 ).…”

Section: Viral Strategies For Counteracting Selective Autophagymentioning

confidence: 99%

Targeting Selective Autophagy as a Therapeutic Strategy for Viral Infectious Diseases

Zhou

et al. 2022

Front. Microbiol.

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Autophagy is an evolutionarily conserved lysosomal degradation system which can recycle multiple cytoplasmic components under both physiological and stressful conditions. Autophagy could be highly selective to deliver different cargoes or substrates, including protein aggregates, pathogenic proteins or superfluous organelles to lysosome using a series of cargo receptor proteins. During viral invasion, cargo receptors selectively target pathogenic components to autolysosome to defense against infection. However, viruses not only evolve different strategies to counteract and escape selective autophagy, but also utilize selective autophagy to restrict antiviral responses to expedite viral replication. Furthermore, several viruses could activate certain forms of selective autophagy, including mitophagy, lipophagy, aggrephagy, and ferritinophagy, for more effective infection and replication. The complicated relationship between selective autophagy and viral infection indicates that selective autophagy may provide potential therapeutic targets for human infectious diseases. In this review, we will summarize the recent progress on the interplay between selective autophagy and host antiviral defense, aiming to arouse the importance of modulating selective autophagy as future therapies toward viral infectious diseases.

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2AB protein of Senecavirus A antagonizes selective autophagy and type I interferon production by degrading LC3 and MARCHF8

Cited by 32 publications

References 50 publications

2B and 3C Proteins of Senecavirus A Antagonize the Antiviral Activity of DDX21 via the Caspase-Dependent Degradation of DDX21

2B and 3C Proteins of Senecavirus A Antagonize the Antiviral Activity of DDX21 via the Caspase-Dependent Degradation of DDX21

Comparative Proteomic Analysis Reveals Mx1 Inhibits Senecavirus A Replication in PK-15 Cells by Interacting with the Capsid Proteins VP1, VP2 and VP3

Targeting Selective Autophagy as a Therapeutic Strategy for Viral Infectious Diseases

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