Mary Wilson
Well-known member
October 16, 2024
https://doi.org/10.1073/pnas.2409132121
Wan Li, Jing Zhou, Yang Gu, Yuheng Chen, Yiming Huang, Jingxin Yang, Xiaojuan Zhu, Kangchen Zhao, Qin Yan, Zongzheng Zhao, Xiao Li, Guochun Chen, Xuemei Jia, Shou-Jiang Gao, and Chun Lu
Significance
DNA herpesviruses and mpox virus (MPXV) represent significant threats to human health. Gaining a deeper understanding of how host innate immunity controls these viral infections is crucial for uncovering disease mechanisms and developing effective strategies for infection management. While the RNA m[SUP]6[/SUP]A demethylase AlkB homolog 5 (ALKBH5) is known to influence innate immunity, the role of novel lysine acylation in modulating ALKBH5-mediated innate immunity remains poorly understood. This study uncovers that establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2) and sirtuin 6 (SIRT6) regulate the lactylation of ALKBH5, which in turn enhances innate immunity against herpesviruses and MPXV by promoting m[SUP]6[/SUP]A-mediated IFN-β mRNA biogenesis. Our findings reveal a unique mechanism of innate immune regulation and highlight the potential for targeting of lysine lactylation as a therapeutic strategy against herpesvirus and MPXV infections.
Abstract
RNA N[SUP]6[/SUP]-methyladenosine (m[SUP]6[/SUP]A) demethylase AlkB homolog 5 (ALKBH5) plays a crucial role in regulating innate immunity. Lysine acylation, a widespread protein modification, influences protein function, but its impact on ALKBH5 during viral infections has not been well characterized. This study investigates the presence and regulatory mechanisms of a previously unidentified lysine acylation in ALKBH5 and its role in mediating m[SUP]6[/SUP]A modifications to activate antiviral innate immune responses. We demonstrate that ALKBH5 undergoes lactylation, which is essential for an effective innate immune response against DNA herpesviruses, including herpes simplex virus type 1 (HSV-1), Kaposi’s sarcoma–associated herpesvirus (KSHV), and mpox virus (MPXV). This lactylation attenuates viral replication. Mechanistically, viral infections enhance ALKBH5 lactylation by increasing its interaction with acetyltransferase ESCO2 and decreasing its interaction with deacetyltransferase SIRT6. Lactylated ALKBH5 binds interferon-beta (IFN-β) messenger RNA (mRNA), leading to demethylation of its m[SUP]6[/SUP]A modifications and promoting IFN-β mRNA biogenesis. Overexpression of ESCO2 or depletion of SIRT6 further enhances ALKBH5 lactylation to strengthen IFN-β mRNA biogenesis. Our results identify a posttranslational modification of ALKBH5 and its role in regulating antiviral innate immune responses through m[SUP]6[/SUP]A modification. The finding provides an understanding of innate immunity and offers a potential therapeutic target for HSV-1, KSHV, and MPXV infections. ...
https://www.pnas.org/doi/10.1073/pnas.2409132121
https://doi.org/10.1073/pnas.2409132121
Wan Li, Jing Zhou, Yang Gu, Yuheng Chen, Yiming Huang, Jingxin Yang, Xiaojuan Zhu, Kangchen Zhao, Qin Yan, Zongzheng Zhao, Xiao Li, Guochun Chen, Xuemei Jia, Shou-Jiang Gao, and Chun Lu
Significance
DNA herpesviruses and mpox virus (MPXV) represent significant threats to human health. Gaining a deeper understanding of how host innate immunity controls these viral infections is crucial for uncovering disease mechanisms and developing effective strategies for infection management. While the RNA m[SUP]6[/SUP]A demethylase AlkB homolog 5 (ALKBH5) is known to influence innate immunity, the role of novel lysine acylation in modulating ALKBH5-mediated innate immunity remains poorly understood. This study uncovers that establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2) and sirtuin 6 (SIRT6) regulate the lactylation of ALKBH5, which in turn enhances innate immunity against herpesviruses and MPXV by promoting m[SUP]6[/SUP]A-mediated IFN-β mRNA biogenesis. Our findings reveal a unique mechanism of innate immune regulation and highlight the potential for targeting of lysine lactylation as a therapeutic strategy against herpesvirus and MPXV infections.
Abstract
RNA N[SUP]6[/SUP]-methyladenosine (m[SUP]6[/SUP]A) demethylase AlkB homolog 5 (ALKBH5) plays a crucial role in regulating innate immunity. Lysine acylation, a widespread protein modification, influences protein function, but its impact on ALKBH5 during viral infections has not been well characterized. This study investigates the presence and regulatory mechanisms of a previously unidentified lysine acylation in ALKBH5 and its role in mediating m[SUP]6[/SUP]A modifications to activate antiviral innate immune responses. We demonstrate that ALKBH5 undergoes lactylation, which is essential for an effective innate immune response against DNA herpesviruses, including herpes simplex virus type 1 (HSV-1), Kaposi’s sarcoma–associated herpesvirus (KSHV), and mpox virus (MPXV). This lactylation attenuates viral replication. Mechanistically, viral infections enhance ALKBH5 lactylation by increasing its interaction with acetyltransferase ESCO2 and decreasing its interaction with deacetyltransferase SIRT6. Lactylated ALKBH5 binds interferon-beta (IFN-β) messenger RNA (mRNA), leading to demethylation of its m[SUP]6[/SUP]A modifications and promoting IFN-β mRNA biogenesis. Overexpression of ESCO2 or depletion of SIRT6 further enhances ALKBH5 lactylation to strengthen IFN-β mRNA biogenesis. Our results identify a posttranslational modification of ALKBH5 and its role in regulating antiviral innate immune responses through m[SUP]6[/SUP]A modification. The finding provides an understanding of innate immunity and offers a potential therapeutic target for HSV-1, KSHV, and MPXV infections. ...
https://www.pnas.org/doi/10.1073/pnas.2409132121