Heat Shock Protein 60 Is Involved in Viral Replication Complex Formation and Facilitates Foot and Mouth Virus Replication by Stabilizing Viral Nonstructural Proteins 3A and 2C
ABSTRACT The maintenance of viral protein homeostasis depends on the machinery of the infected host cells, giving us an insight into the interplay between host and virus. Accumulating evidence suggests that heat shock protein 60 (HSP60), as one molecular chaperone, is involved in regulating virus in...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-10-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.01434-22 |
| _version_ | 1797989760880345088 |
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| author | Jianli Tang Sahibzada Waheed Abdullah Pinghua Li Jin'en Wu Chenchen Pei Suyu Mu Yunlu Wang Shiqi Sun Huichen Guo |
| author_facet | Jianli Tang Sahibzada Waheed Abdullah Pinghua Li Jin'en Wu Chenchen Pei Suyu Mu Yunlu Wang Shiqi Sun Huichen Guo |
| author_sort | Jianli Tang |
| collection | DOAJ |
| description | ABSTRACT The maintenance of viral protein homeostasis depends on the machinery of the infected host cells, giving us an insight into the interplay between host and virus. Accumulating evidence suggests that heat shock protein 60 (HSP60), as one molecular chaperone, is involved in regulating virus infection. However, the role of HSP60 during foot-and-mouth disease virus (FMDV) replication and its specific mechanisms have not been reported. We demonstrate that HSP60 modulates the FMDV life cycle. HSP60 plays a role at the postentry stage of the viral life cycle, including RNA replication and mRNA translation; however, HSP60 does not affect viral replication of Seneca Valley virus (SVA) or encephalomyocarditis virus (EMCV). We found that HSP60 is involved in FMDV replication complex (RC) formation. Furthermore, our results indicate that HSP60 interacts with FMDV nonstructural proteins 3A and 2C, key elements of the viral replication complex. We also show that HSP60 regulates the stability of 3A and 2C via caspase-dependent and autophagy-lysosome-dependent degradation, thereby promoting FMDV RNA synthesis and mRNA translation mediated by the RC. Additionally, we determined that the apical domain of HSP60 is responsible for interacting with 3A and 2C. The N terminus of 3A and ATPase domain of 2C are involved in binding to HSP60. Importantly, HSP60 depletion potently reduced FMDV pathogenicity in infected mice. Altogether, this study demonstrates a specific role of HSP60 in promoting FMDV replication. Furthermore, targeting host HSP60 will help us design the FMDV-specific antiviral drugs. IMPORTANCE FMDV is the leading cause of the foot-and-mouth disease (FMD), affecting cloven-hoofed animals with high morbidity and mortality. We determined that HSP60 is required for efficient viral RNA replication and mRNA translation during FMDV infection. Furthermore, we demonstrate that HSP60 interacts with FMDV nonstructural proteins 3A and 2C, the elements of the RC; HSP60 contributes to the stability of 3A and 2C to affect the formation and function of the RC. We also validated the potential role of HSP60 as the antiviral target in vivo using small interfering RNA. These findings deepen the understanding of the host-virus interaction and provide information supporting the design of novel therapeutics for FMDV infection. |
| first_indexed | 2024-04-11T08:25:30Z |
| format | Article |
| id | doaj.art-507b8f1b8a674f548157d8f30e9a6fcd |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-11T08:25:30Z |
| publishDate | 2022-10-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-507b8f1b8a674f548157d8f30e9a6fcd2022-12-22T04:34:47ZengAmerican Society for MicrobiologymBio2150-75112022-10-0113510.1128/mbio.01434-22Heat Shock Protein 60 Is Involved in Viral Replication Complex Formation and Facilitates Foot and Mouth Virus Replication by Stabilizing Viral Nonstructural Proteins 3A and 2CJianli Tang0Sahibzada Waheed Abdullah1Pinghua Li2Jin'en Wu3Chenchen Pei4Suyu Mu5Yunlu Wang6Shiqi Sun7Huichen Guo8State Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, ChinaState Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, ChinaState Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, ChinaState Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, ChinaState Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, ChinaState Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, ChinaCollege of Animal Science, University of Tibet Agricultural and Animal Husbandry, Linzhi, Tibet, ChinaState Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, ChinaState Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, ChinaABSTRACT The maintenance of viral protein homeostasis depends on the machinery of the infected host cells, giving us an insight into the interplay between host and virus. Accumulating evidence suggests that heat shock protein 60 (HSP60), as one molecular chaperone, is involved in regulating virus infection. However, the role of HSP60 during foot-and-mouth disease virus (FMDV) replication and its specific mechanisms have not been reported. We demonstrate that HSP60 modulates the FMDV life cycle. HSP60 plays a role at the postentry stage of the viral life cycle, including RNA replication and mRNA translation; however, HSP60 does not affect viral replication of Seneca Valley virus (SVA) or encephalomyocarditis virus (EMCV). We found that HSP60 is involved in FMDV replication complex (RC) formation. Furthermore, our results indicate that HSP60 interacts with FMDV nonstructural proteins 3A and 2C, key elements of the viral replication complex. We also show that HSP60 regulates the stability of 3A and 2C via caspase-dependent and autophagy-lysosome-dependent degradation, thereby promoting FMDV RNA synthesis and mRNA translation mediated by the RC. Additionally, we determined that the apical domain of HSP60 is responsible for interacting with 3A and 2C. The N terminus of 3A and ATPase domain of 2C are involved in binding to HSP60. Importantly, HSP60 depletion potently reduced FMDV pathogenicity in infected mice. Altogether, this study demonstrates a specific role of HSP60 in promoting FMDV replication. Furthermore, targeting host HSP60 will help us design the FMDV-specific antiviral drugs. IMPORTANCE FMDV is the leading cause of the foot-and-mouth disease (FMD), affecting cloven-hoofed animals with high morbidity and mortality. We determined that HSP60 is required for efficient viral RNA replication and mRNA translation during FMDV infection. Furthermore, we demonstrate that HSP60 interacts with FMDV nonstructural proteins 3A and 2C, the elements of the RC; HSP60 contributes to the stability of 3A and 2C to affect the formation and function of the RC. We also validated the potential role of HSP60 as the antiviral target in vivo using small interfering RNA. These findings deepen the understanding of the host-virus interaction and provide information supporting the design of novel therapeutics for FMDV infection.https://journals.asm.org/doi/10.1128/mbio.01434-22HSP60FMDV3A2Creplication complex |
| spellingShingle | Jianli Tang Sahibzada Waheed Abdullah Pinghua Li Jin'en Wu Chenchen Pei Suyu Mu Yunlu Wang Shiqi Sun Huichen Guo Heat Shock Protein 60 Is Involved in Viral Replication Complex Formation and Facilitates Foot and Mouth Virus Replication by Stabilizing Viral Nonstructural Proteins 3A and 2C mBio HSP60 FMDV 3A 2C replication complex |
| title | Heat Shock Protein 60 Is Involved in Viral Replication Complex Formation and Facilitates Foot and Mouth Virus Replication by Stabilizing Viral Nonstructural Proteins 3A and 2C |
| title_full | Heat Shock Protein 60 Is Involved in Viral Replication Complex Formation and Facilitates Foot and Mouth Virus Replication by Stabilizing Viral Nonstructural Proteins 3A and 2C |
| title_fullStr | Heat Shock Protein 60 Is Involved in Viral Replication Complex Formation and Facilitates Foot and Mouth Virus Replication by Stabilizing Viral Nonstructural Proteins 3A and 2C |
| title_full_unstemmed | Heat Shock Protein 60 Is Involved in Viral Replication Complex Formation and Facilitates Foot and Mouth Virus Replication by Stabilizing Viral Nonstructural Proteins 3A and 2C |
| title_short | Heat Shock Protein 60 Is Involved in Viral Replication Complex Formation and Facilitates Foot and Mouth Virus Replication by Stabilizing Viral Nonstructural Proteins 3A and 2C |
| title_sort | heat shock protein 60 is involved in viral replication complex formation and facilitates foot and mouth virus replication by stabilizing viral nonstructural proteins 3a and 2c |
| topic | HSP60 FMDV 3A 2C replication complex |
| url | https://journals.asm.org/doi/10.1128/mbio.01434-22 |
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