MARCH8 Restricts RSV Replication by Promoting Cellular Apoptosis Through Ubiquitin-Mediated Proteolysis of Viral SH Protein
Numerous host factors function as intrinsic antiviral effectors to attenuate viral replication. MARCH8 is an E3 ubiquitin ligase that has been identified as a host restriction factor that inhibits the replication of various viruses. This study elucidated the mechanism by which MARCH8 restricts respi...
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2024-12-01
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| author | Takashi Okura Tatsuki Takahashi Taichi Kameya Fuminori Mizukoshi Yusuke Nakai Masatoshi Kakizaki Mayuko Nishi Noriyuki Otsuki Hirokazu Kimura Kei Miyakawa Kazuya Shirato Wataru Kamitani Akihide Ryo |
| author_facet | Takashi Okura Tatsuki Takahashi Taichi Kameya Fuminori Mizukoshi Yusuke Nakai Masatoshi Kakizaki Mayuko Nishi Noriyuki Otsuki Hirokazu Kimura Kei Miyakawa Kazuya Shirato Wataru Kamitani Akihide Ryo |
| author_sort | Takashi Okura |
| collection | DOAJ |
| description | Numerous host factors function as intrinsic antiviral effectors to attenuate viral replication. MARCH8 is an E3 ubiquitin ligase that has been identified as a host restriction factor that inhibits the replication of various viruses. This study elucidated the mechanism by which MARCH8 restricts respiratory syncytial virus (RSV) replication through selective degradation of the viral small hydrophobic (SH) protein. We demonstrated that MARCH8 directly interacts with RSV-SH and catalyzes its ubiquitination at lysine 13, leading to SH degradation via the ubiquitin-lysosomal pathway. Functionally, MARCH8 expression enhances RSV-induced apoptosis through SH degradation, ultimately reducing viral titers. Conversely, an RSV strain harboring the SH-K13R mutation exhibited prolonged SH protein stability and attenuated apoptosis in infected cells, even in the presence of MARCH8. Targeted depletion of MARCH8 enhances cellular survival and potentially increases viral persistence. These findings demonstrate that MARCH8 promotes the early elimination of virus-infected cells by abrogating the anti-apoptotic function of SH, thereby reducing viral transmission. Our study provides novel insights into the interplay between host restriction factors and viral evasion strategies, potentially providing new therapeutic approaches for RSV infections. |
| format | Article |
| id | doaj-art-0145bd505d1948cd867f7dc5c93e4bc4 |
| institution | DOAJ |
| issn | 1999-4915 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
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| series | Viruses |
| spelling | doaj-art-0145bd505d1948cd867f7dc5c93e4bc42025-08-20T02:56:55ZengMDPI AGViruses1999-49152024-12-011612193510.3390/v16121935MARCH8 Restricts RSV Replication by Promoting Cellular Apoptosis Through Ubiquitin-Mediated Proteolysis of Viral SH ProteinTakashi Okura0Tatsuki Takahashi1Taichi Kameya2Fuminori Mizukoshi3Yusuke Nakai4Masatoshi Kakizaki5Mayuko Nishi6Noriyuki Otsuki7Hirokazu Kimura8Kei Miyakawa9Kazuya Shirato10Wataru Kamitani11Akihide Ryo12Department of Virology 3, National Institute of Infectious Diseases, Musashimurayama 208-0011, Tokyo, JapanDepartment of Infectious Diseases and Host Defense, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Gunma, JapanDepartment of Virology 3, National Institute of Infectious Diseases, Musashimurayama 208-0011, Tokyo, JapanDepartment of Virology 3, National Institute of Infectious Diseases, Musashimurayama 208-0011, Tokyo, JapanDepartment of Virology 3, National Institute of Infectious Diseases, Musashimurayama 208-0011, Tokyo, JapanDepartment of Virology 3, National Institute of Infectious Diseases, Musashimurayama 208-0011, Tokyo, JapanDepartment of Virology 3, National Institute of Infectious Diseases, Musashimurayama 208-0011, Tokyo, JapanDepartment of Virology 3, National Institute of Infectious Diseases, Musashimurayama 208-0011, Tokyo, JapanDepartment of Health Science, Graduate School of Health Sciences, Gunma Paz University, Takasaki 370-0006, Gunma, JapanResearch Center for Influenza and Respiratory Viruses, National Institute of Infectious Diseases, Musashimurayama 208-0011, Tokyo, JapanDepartment of Virology 3, National Institute of Infectious Diseases, Musashimurayama 208-0011, Tokyo, JapanDepartment of Infectious Diseases and Host Defense, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Gunma, JapanDepartment of Virology 3, National Institute of Infectious Diseases, Musashimurayama 208-0011, Tokyo, JapanNumerous host factors function as intrinsic antiviral effectors to attenuate viral replication. MARCH8 is an E3 ubiquitin ligase that has been identified as a host restriction factor that inhibits the replication of various viruses. This study elucidated the mechanism by which MARCH8 restricts respiratory syncytial virus (RSV) replication through selective degradation of the viral small hydrophobic (SH) protein. We demonstrated that MARCH8 directly interacts with RSV-SH and catalyzes its ubiquitination at lysine 13, leading to SH degradation via the ubiquitin-lysosomal pathway. Functionally, MARCH8 expression enhances RSV-induced apoptosis through SH degradation, ultimately reducing viral titers. Conversely, an RSV strain harboring the SH-K13R mutation exhibited prolonged SH protein stability and attenuated apoptosis in infected cells, even in the presence of MARCH8. Targeted depletion of MARCH8 enhances cellular survival and potentially increases viral persistence. These findings demonstrate that MARCH8 promotes the early elimination of virus-infected cells by abrogating the anti-apoptotic function of SH, thereby reducing viral transmission. Our study provides novel insights into the interplay between host restriction factors and viral evasion strategies, potentially providing new therapeutic approaches for RSV infections.https://www.mdpi.com/1999-4915/16/12/1935respiratory syncytial virussmall hydrophobic proteinMARCH8ubiquitinationapoptosis |
| spellingShingle | Takashi Okura Tatsuki Takahashi Taichi Kameya Fuminori Mizukoshi Yusuke Nakai Masatoshi Kakizaki Mayuko Nishi Noriyuki Otsuki Hirokazu Kimura Kei Miyakawa Kazuya Shirato Wataru Kamitani Akihide Ryo MARCH8 Restricts RSV Replication by Promoting Cellular Apoptosis Through Ubiquitin-Mediated Proteolysis of Viral SH Protein Viruses respiratory syncytial virus small hydrophobic protein MARCH8 ubiquitination apoptosis |
| title | MARCH8 Restricts RSV Replication by Promoting Cellular Apoptosis Through Ubiquitin-Mediated Proteolysis of Viral SH Protein |
| title_full | MARCH8 Restricts RSV Replication by Promoting Cellular Apoptosis Through Ubiquitin-Mediated Proteolysis of Viral SH Protein |
| title_fullStr | MARCH8 Restricts RSV Replication by Promoting Cellular Apoptosis Through Ubiquitin-Mediated Proteolysis of Viral SH Protein |
| title_full_unstemmed | MARCH8 Restricts RSV Replication by Promoting Cellular Apoptosis Through Ubiquitin-Mediated Proteolysis of Viral SH Protein |
| title_short | MARCH8 Restricts RSV Replication by Promoting Cellular Apoptosis Through Ubiquitin-Mediated Proteolysis of Viral SH Protein |
| title_sort | march8 restricts rsv replication by promoting cellular apoptosis through ubiquitin mediated proteolysis of viral sh protein |
| topic | respiratory syncytial virus small hydrophobic protein MARCH8 ubiquitination apoptosis |
| url | https://www.mdpi.com/1999-4915/16/12/1935 |
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