METTL16 controls Kaposi’s sarcoma-associated herpesvirus replication by regulating S-adenosylmethionine cycle
Abstract Oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) consists of latent and lytic replication phases, both of which are important for the development of KSHV-related cancers. As one of the most abundant RNA modifications, N 6 -methyladenosine (m6A) and its related complexes regulate KSH...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-09-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06121-3 |
| _version_ | 1797689081540378624 |
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| author | Xinquan Zhang Wen Meng Jian Feng Xinghong Gao Chao Qin Pinghui Feng Yufei Huang Shou-Jiang Gao |
| author_facet | Xinquan Zhang Wen Meng Jian Feng Xinghong Gao Chao Qin Pinghui Feng Yufei Huang Shou-Jiang Gao |
| author_sort | Xinquan Zhang |
| collection | DOAJ |
| description | Abstract Oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) consists of latent and lytic replication phases, both of which are important for the development of KSHV-related cancers. As one of the most abundant RNA modifications, N 6 -methyladenosine (m6A) and its related complexes regulate KSHV life cycle. However, the role of METTL16, a newly discovered RNA methyltransferase, in KSHV life cycle remains unknown. In this study, we have identified a suppressive role of METTL16 in KSHV lytic replication. METTL16 knockdown increased while METTL16 overexpression reduced KSHV lytic replication. METTL16 binding to and writing of m6A on MAT2A transcript are essential for its splicing, maturation and expression. As a rate-limiting enzyme in the methionine-S-adenosylmethionine (SAM) cycle, MAT2A catalyzes the conversion of L-methionine to SAM required for the transmethylation of protein, DNA and RNA, transamination of polyamines, and transsulfuration of cystathionine. Consequently, knockdown or chemical inhibition of MAT2A reduced intracellular SAM level and enhanced KSHV lytic replication. In contrast, SAM treatment was sufficient to inhibit KSHV lytic replication and reverse the effect of the enhanced KSHV lytic program caused by METTL16 or MAT2A knockdown. Mechanistically, METTL16 or MAT2A knockdown increased while SAM treatment decreased the intracellular reactive oxygen species level by altering glutathione level, which is essential for efficient KSHV lytic replication. These findings demonstrate that METTL16 suppresses KSHV lytic replication by modulating the SAM cycle to maintain intracellular SAM level and redox homeostasis, thus illustrating the linkage of KSHV life cycle with specific m6A modifications, and cellular metabolic and oxidative conditions. |
| first_indexed | 2024-03-12T01:40:59Z |
| format | Article |
| id | doaj.art-e978095b0626445eb2f0ae4549a4789e |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-12T01:40:59Z |
| publishDate | 2023-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-e978095b0626445eb2f0ae4549a4789e2023-09-10T11:28:09ZengNature Publishing GroupCell Death and Disease2041-48892023-09-0114911310.1038/s41419-023-06121-3METTL16 controls Kaposi’s sarcoma-associated herpesvirus replication by regulating S-adenosylmethionine cycleXinquan Zhang0Wen Meng1Jian Feng2Xinghong Gao3Chao Qin4Pinghui Feng5Yufei Huang6Shou-Jiang Gao7Cancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer CenterCancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer CenterCancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer CenterCancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer CenterSection of Infection and Immunity, Herman Ostrow School of Dentistry, Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern CaliforniaSection of Infection and Immunity, Herman Ostrow School of Dentistry, Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern CaliforniaCancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer CenterCancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer CenterAbstract Oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) consists of latent and lytic replication phases, both of which are important for the development of KSHV-related cancers. As one of the most abundant RNA modifications, N 6 -methyladenosine (m6A) and its related complexes regulate KSHV life cycle. However, the role of METTL16, a newly discovered RNA methyltransferase, in KSHV life cycle remains unknown. In this study, we have identified a suppressive role of METTL16 in KSHV lytic replication. METTL16 knockdown increased while METTL16 overexpression reduced KSHV lytic replication. METTL16 binding to and writing of m6A on MAT2A transcript are essential for its splicing, maturation and expression. As a rate-limiting enzyme in the methionine-S-adenosylmethionine (SAM) cycle, MAT2A catalyzes the conversion of L-methionine to SAM required for the transmethylation of protein, DNA and RNA, transamination of polyamines, and transsulfuration of cystathionine. Consequently, knockdown or chemical inhibition of MAT2A reduced intracellular SAM level and enhanced KSHV lytic replication. In contrast, SAM treatment was sufficient to inhibit KSHV lytic replication and reverse the effect of the enhanced KSHV lytic program caused by METTL16 or MAT2A knockdown. Mechanistically, METTL16 or MAT2A knockdown increased while SAM treatment decreased the intracellular reactive oxygen species level by altering glutathione level, which is essential for efficient KSHV lytic replication. These findings demonstrate that METTL16 suppresses KSHV lytic replication by modulating the SAM cycle to maintain intracellular SAM level and redox homeostasis, thus illustrating the linkage of KSHV life cycle with specific m6A modifications, and cellular metabolic and oxidative conditions.https://doi.org/10.1038/s41419-023-06121-3 |
| spellingShingle | Xinquan Zhang Wen Meng Jian Feng Xinghong Gao Chao Qin Pinghui Feng Yufei Huang Shou-Jiang Gao METTL16 controls Kaposi’s sarcoma-associated herpesvirus replication by regulating S-adenosylmethionine cycle Cell Death and Disease |
| title | METTL16 controls Kaposi’s sarcoma-associated herpesvirus replication by regulating S-adenosylmethionine cycle |
| title_full | METTL16 controls Kaposi’s sarcoma-associated herpesvirus replication by regulating S-adenosylmethionine cycle |
| title_fullStr | METTL16 controls Kaposi’s sarcoma-associated herpesvirus replication by regulating S-adenosylmethionine cycle |
| title_full_unstemmed | METTL16 controls Kaposi’s sarcoma-associated herpesvirus replication by regulating S-adenosylmethionine cycle |
| title_short | METTL16 controls Kaposi’s sarcoma-associated herpesvirus replication by regulating S-adenosylmethionine cycle |
| title_sort | mettl16 controls kaposi s sarcoma associated herpesvirus replication by regulating s adenosylmethionine cycle |
| url | https://doi.org/10.1038/s41419-023-06121-3 |
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