The P132H mutation of SARS-CoV-2 NSP5 relieves its inhibition on interferon-β activation via blocking MAVS degradation
Abstract The prevalence of the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important transition in the epidemic of coronavirus disease 2019 (COVID-19). Compared with other SARS-CoV-2 variants, Omicron and its subvariants exhibit decreased pathogenicity, thus...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer
2025-07-01
|
| Series: | Cellular and Molecular Life Sciences |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s00018-025-05822-6 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849766636112838656 |
|---|---|
| author | Yuxin Zhang Tong-Yun Wang Huihui Yan Zhoule Guo Zhonghao Lian Hailan Yao Shuofeng Yuan Xing-Yi Ge Ye Qiu |
| author_facet | Yuxin Zhang Tong-Yun Wang Huihui Yan Zhoule Guo Zhonghao Lian Hailan Yao Shuofeng Yuan Xing-Yi Ge Ye Qiu |
| author_sort | Yuxin Zhang |
| collection | DOAJ |
| description | Abstract The prevalence of the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important transition in the epidemic of coronavirus disease 2019 (COVID-19). Compared with other SARS-CoV-2 variants, Omicron and its subvariants exhibit decreased pathogenicity, thus contributing to the moderation of the epidemic. However, the mechanism underlying such changes is not fully understood. NSP5 is a SARS-CoV-2-encoded protease that counteracts antiviral immunity, and the P132H mutation of NSP5 is present exclusively in Omicron and its subvariants. In this study, we found that this mutation solely relieved cytopathogenicity and reduced the viral replication during SARS-CoV-2 infection. Further studies suggested that P132H blocked the NSP5-mediated degradation of MAVS by impairing the K136-linked ubiquitination of MAVS, thus restoring the IFN-β activation inhibited by NSP5. Structural analysis in silico suggested that P132H disrupted multiple hydrogen bonds between NSP5 and UbcH5b, an E2 ubiquitin-conjugating enzyme required for K136 ubiquitination. In summary, our results provide a potential mechanism explaining the decreased pathogenicity of the Omicron variant of SARS-CoV-2. |
| format | Article |
| id | doaj-art-eb1640d957f14b289fb4e7494be92468 |
| institution | DOAJ |
| issn | 1420-9071 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Springer |
| record_format | Article |
| series | Cellular and Molecular Life Sciences |
| spelling | doaj-art-eb1640d957f14b289fb4e7494be924682025-08-20T03:04:30ZengSpringerCellular and Molecular Life Sciences1420-90712025-07-0182111810.1007/s00018-025-05822-6The P132H mutation of SARS-CoV-2 NSP5 relieves its inhibition on interferon-β activation via blocking MAVS degradationYuxin Zhang0Tong-Yun Wang1Huihui Yan2Zhoule Guo3Zhonghao Lian4Hailan Yao5Shuofeng Yuan6Xing-Yi Ge7Ye Qiu8Hunan Provincial Key Laboratory of Medical Virology and Hunan Research Center of the Basic Discipline for Cell Signaling, College of Biology, Hunan UniversityDivision of Genetics, Department of Pediatrics, Program in Immunology, Bioinformatics and Systems Biology Program, Institute for Genomic Medicine, University of California San DiegoHunan Provincial Key Laboratory of Medical Virology and Hunan Research Center of the Basic Discipline for Cell Signaling, College of Biology, Hunan UniversityHunan Provincial Key Laboratory of Medical Virology and Hunan Research Center of the Basic Discipline for Cell Signaling, College of Biology, Hunan UniversityHunan Provincial Key Laboratory of Medical Virology and Hunan Research Center of the Basic Discipline for Cell Signaling, College of Biology, Hunan UniversityDepartment of Biochemistry & Immunology, Capital Institute of PediatricsState Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, Carol Yu Centre for Infection, The University of Hong KongHunan Provincial Key Laboratory of Medical Virology and Hunan Research Center of the Basic Discipline for Cell Signaling, College of Biology, Hunan UniversityHunan Provincial Key Laboratory of Medical Virology and Hunan Research Center of the Basic Discipline for Cell Signaling, College of Biology, Hunan UniversityAbstract The prevalence of the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important transition in the epidemic of coronavirus disease 2019 (COVID-19). Compared with other SARS-CoV-2 variants, Omicron and its subvariants exhibit decreased pathogenicity, thus contributing to the moderation of the epidemic. However, the mechanism underlying such changes is not fully understood. NSP5 is a SARS-CoV-2-encoded protease that counteracts antiviral immunity, and the P132H mutation of NSP5 is present exclusively in Omicron and its subvariants. In this study, we found that this mutation solely relieved cytopathogenicity and reduced the viral replication during SARS-CoV-2 infection. Further studies suggested that P132H blocked the NSP5-mediated degradation of MAVS by impairing the K136-linked ubiquitination of MAVS, thus restoring the IFN-β activation inhibited by NSP5. Structural analysis in silico suggested that P132H disrupted multiple hydrogen bonds between NSP5 and UbcH5b, an E2 ubiquitin-conjugating enzyme required for K136 ubiquitination. In summary, our results provide a potential mechanism explaining the decreased pathogenicity of the Omicron variant of SARS-CoV-2.https://doi.org/10.1007/s00018-025-05822-6SARS-CoV-2 variantsP132HIFN-βMAVSNSP5 |
| spellingShingle | Yuxin Zhang Tong-Yun Wang Huihui Yan Zhoule Guo Zhonghao Lian Hailan Yao Shuofeng Yuan Xing-Yi Ge Ye Qiu The P132H mutation of SARS-CoV-2 NSP5 relieves its inhibition on interferon-β activation via blocking MAVS degradation Cellular and Molecular Life Sciences SARS-CoV-2 variants P132H IFN-β MAVS NSP5 |
| title | The P132H mutation of SARS-CoV-2 NSP5 relieves its inhibition on interferon-β activation via blocking MAVS degradation |
| title_full | The P132H mutation of SARS-CoV-2 NSP5 relieves its inhibition on interferon-β activation via blocking MAVS degradation |
| title_fullStr | The P132H mutation of SARS-CoV-2 NSP5 relieves its inhibition on interferon-β activation via blocking MAVS degradation |
| title_full_unstemmed | The P132H mutation of SARS-CoV-2 NSP5 relieves its inhibition on interferon-β activation via blocking MAVS degradation |
| title_short | The P132H mutation of SARS-CoV-2 NSP5 relieves its inhibition on interferon-β activation via blocking MAVS degradation |
| title_sort | p132h mutation of sars cov 2 nsp5 relieves its inhibition on interferon β activation via blocking mavs degradation |
| topic | SARS-CoV-2 variants P132H IFN-β MAVS NSP5 |
| url | https://doi.org/10.1007/s00018-025-05822-6 |
| work_keys_str_mv | AT yuxinzhang thep132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT tongyunwang thep132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT huihuiyan thep132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT zhouleguo thep132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT zhonghaolian thep132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT hailanyao thep132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT shuofengyuan thep132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT xingyige thep132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT yeqiu thep132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT yuxinzhang p132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT tongyunwang p132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT huihuiyan p132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT zhouleguo p132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT zhonghaolian p132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT hailanyao p132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT shuofengyuan p132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT xingyige p132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation AT yeqiu p132hmutationofsarscov2nsp5relievesitsinhibitiononinterferonbactivationviablockingmavsdegradation |