The Deubiquitinase USP29 Promotes SARS-CoV-2 Virulence by Preventing Proteasome Degradation of ORF9b
ABSTRACT Ubiquitin signaling is essential for immunity to restrict pathogen proliferation. Due to its enormous impact on human health and the global economy, intensive efforts have been invested in studying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its interactions with hosts....
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-06-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.01300-22 |
| _version_ | 1818249299415269376 |
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| author | Wenying Gao Liuli Wang Xiaohui Ju Simin Zhao Zhaolong Li Manman Su Jiancheng Xu Peihui Wang Qiang Ding Guoyue Lv Wenyan Zhang |
| author_facet | Wenying Gao Liuli Wang Xiaohui Ju Simin Zhao Zhaolong Li Manman Su Jiancheng Xu Peihui Wang Qiang Ding Guoyue Lv Wenyan Zhang |
| author_sort | Wenying Gao |
| collection | DOAJ |
| description | ABSTRACT Ubiquitin signaling is essential for immunity to restrict pathogen proliferation. Due to its enormous impact on human health and the global economy, intensive efforts have been invested in studying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its interactions with hosts. However, the role of the ubiquitin network in pathogenicity has not yet been explored. Here, we found that ORF9b of SARS-CoV-2 is ubiquitinated on Lys-4 and Lys-40 by unknown E3 ubiquitin ligases and is degraded by the ubiquitin proteasomal system. Importantly, we identified USP29 as a host factor that prevents ORF9b ubiquitination and subsequent degradation. USP29 interacts with the carboxyl end of ORF9b and removes ubiquitin chains from the protein, thereby inhibiting type I interferon (IFN) induction and NF-κB activation. We also found that ORF9b stabilization by USP29 enhanced the virulence of VSV-eGFP and transcription and replication-competent SARS-CoV-2 virus-like-particles (trVLP). Moreover, we observed that the mRNA level of USP29 in SARS-CoV-2 patients was higher than that in healthy people. Our findings provide important evidence indicating that targeting USP29 may effectively combat SARS-CoV-2 infection. IMPORTANCE Coronavirus disease 2019 (COVID-19) is a current global health threat caused by SARS-CoV-2. The innate immune response such as type I IFN (IFN-I) is the first line of host defense against viral infections, whereas SARS-CoV-2 proteins antagonize IFN-I production through distinct mechanisms. Among them, ORF9b inhibits the canonical IκB kinase alpha (IKKɑ)/β/γ-NF-κB signaling and subsequent IFN production; therefore, discovering the regulation of ORF9b by the host might help develop a novel antiviral strategy. Posttranslational modification of proteins by ubiquitination regulates many biological processes, including viral infections. Here, we report that ORF9b is ubiquitinated and degraded through the proteasome pathway, whereas deubiquitinase USP29 deubiquitinates ORF9b and prevents its degradation, resulting in the enhancement of ORF9b-mediated inhibition of IFN-I and NF-κB activation and the enhancement of virulence of VSV-eGFP and SARS-CoV-2 trVLP. |
| first_indexed | 2024-12-12T15:34:17Z |
| format | Article |
| id | doaj.art-72900553112b4477af614a7f8aa4181e |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-12T15:34:17Z |
| publishDate | 2022-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-72900553112b4477af614a7f8aa4181e2022-12-22T00:20:03ZengAmerican Society for MicrobiologymBio2150-75112022-06-0113310.1128/mbio.01300-22The Deubiquitinase USP29 Promotes SARS-CoV-2 Virulence by Preventing Proteasome Degradation of ORF9bWenying Gao0Liuli Wang1Xiaohui Ju2Simin Zhao3Zhaolong Li4Manman Su5Jiancheng Xu6Peihui Wang7Qiang Ding8Guoyue Lv9Wenyan Zhang10Center of Infectious Diseases and Pathogen Biology, Institute of Virology and AIDS Research, Key Laboratory of Organ Regeneration and Transplantation of The Ministry of Education, The First Hospital of Jilin University, Changchun, ChinaCollege of Medicine, Jilin University, Changchun, ChinaSchool of Medicine, Tsinghua University, Beijing, ChinaCenter of Infectious Diseases and Pathogen Biology, Institute of Virology and AIDS Research, Key Laboratory of Organ Regeneration and Transplantation of The Ministry of Education, The First Hospital of Jilin University, Changchun, ChinaCenter of Infectious Diseases and Pathogen Biology, Institute of Virology and AIDS Research, Key Laboratory of Organ Regeneration and Transplantation of The Ministry of Education, The First Hospital of Jilin University, Changchun, ChinaCollege of Medicine, Jilin University, Changchun, ChinaDepartment of Laboratory Medicine, First Hospital of Jilin University, Changchun, ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, ChinaSchool of Medicine, Tsinghua University, Beijing, ChinaDepartment of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin, ChinaCenter of Infectious Diseases and Pathogen Biology, Institute of Virology and AIDS Research, Key Laboratory of Organ Regeneration and Transplantation of The Ministry of Education, The First Hospital of Jilin University, Changchun, ChinaABSTRACT Ubiquitin signaling is essential for immunity to restrict pathogen proliferation. Due to its enormous impact on human health and the global economy, intensive efforts have been invested in studying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its interactions with hosts. However, the role of the ubiquitin network in pathogenicity has not yet been explored. Here, we found that ORF9b of SARS-CoV-2 is ubiquitinated on Lys-4 and Lys-40 by unknown E3 ubiquitin ligases and is degraded by the ubiquitin proteasomal system. Importantly, we identified USP29 as a host factor that prevents ORF9b ubiquitination and subsequent degradation. USP29 interacts with the carboxyl end of ORF9b and removes ubiquitin chains from the protein, thereby inhibiting type I interferon (IFN) induction and NF-κB activation. We also found that ORF9b stabilization by USP29 enhanced the virulence of VSV-eGFP and transcription and replication-competent SARS-CoV-2 virus-like-particles (trVLP). Moreover, we observed that the mRNA level of USP29 in SARS-CoV-2 patients was higher than that in healthy people. Our findings provide important evidence indicating that targeting USP29 may effectively combat SARS-CoV-2 infection. IMPORTANCE Coronavirus disease 2019 (COVID-19) is a current global health threat caused by SARS-CoV-2. The innate immune response such as type I IFN (IFN-I) is the first line of host defense against viral infections, whereas SARS-CoV-2 proteins antagonize IFN-I production through distinct mechanisms. Among them, ORF9b inhibits the canonical IκB kinase alpha (IKKɑ)/β/γ-NF-κB signaling and subsequent IFN production; therefore, discovering the regulation of ORF9b by the host might help develop a novel antiviral strategy. Posttranslational modification of proteins by ubiquitination regulates many biological processes, including viral infections. Here, we report that ORF9b is ubiquitinated and degraded through the proteasome pathway, whereas deubiquitinase USP29 deubiquitinates ORF9b and prevents its degradation, resulting in the enhancement of ORF9b-mediated inhibition of IFN-I and NF-κB activation and the enhancement of virulence of VSV-eGFP and SARS-CoV-2 trVLP.https://journals.asm.org/doi/10.1128/mbio.01300-22SARS-CoV-2ORF9bdegradationUSP29deubiquitination |
| spellingShingle | Wenying Gao Liuli Wang Xiaohui Ju Simin Zhao Zhaolong Li Manman Su Jiancheng Xu Peihui Wang Qiang Ding Guoyue Lv Wenyan Zhang The Deubiquitinase USP29 Promotes SARS-CoV-2 Virulence by Preventing Proteasome Degradation of ORF9b mBio SARS-CoV-2 ORF9b degradation USP29 deubiquitination |
| title | The Deubiquitinase USP29 Promotes SARS-CoV-2 Virulence by Preventing Proteasome Degradation of ORF9b |
| title_full | The Deubiquitinase USP29 Promotes SARS-CoV-2 Virulence by Preventing Proteasome Degradation of ORF9b |
| title_fullStr | The Deubiquitinase USP29 Promotes SARS-CoV-2 Virulence by Preventing Proteasome Degradation of ORF9b |
| title_full_unstemmed | The Deubiquitinase USP29 Promotes SARS-CoV-2 Virulence by Preventing Proteasome Degradation of ORF9b |
| title_short | The Deubiquitinase USP29 Promotes SARS-CoV-2 Virulence by Preventing Proteasome Degradation of ORF9b |
| title_sort | deubiquitinase usp29 promotes sars cov 2 virulence by preventing proteasome degradation of orf9b |
| topic | SARS-CoV-2 ORF9b degradation USP29 deubiquitination |
| url | https://journals.asm.org/doi/10.1128/mbio.01300-22 |
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