Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation
Abstract Cyclic GMP–AMP synthase (cGAS), initially identified as a cytosolic DNA sensor, detects DNA fragments to trigger an innate immune response. Recently, accumulating evidence reveals the presence of cGAS within the nucleus. However, the biological functions of nuclear cGAS are not fully unders...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-12-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-43001-y |
| _version_ | 1827581514654679040 |
|---|---|
| author | Zhengyi Zhen Yu Chen Haiyan Wang Huanyin Tang Haiping Zhang Haipeng Liu Ying Jiang Zhiyong Mao |
| author_facet | Zhengyi Zhen Yu Chen Haiyan Wang Huanyin Tang Haiping Zhang Haipeng Liu Ying Jiang Zhiyong Mao |
| author_sort | Zhengyi Zhen |
| collection | DOAJ |
| description | Abstract Cyclic GMP–AMP synthase (cGAS), initially identified as a cytosolic DNA sensor, detects DNA fragments to trigger an innate immune response. Recently, accumulating evidence reveals the presence of cGAS within the nucleus. However, the biological functions of nuclear cGAS are not fully understood. Here, we demonstrate that nuclear cGAS represses LINE-1 (L1) retrotransposition to preserve genome integrity in human cells. Mechanistically, the E3 ligase TRIM41 interacts with and ubiquitinates ORF2p to influence its stability, and cGAS enhances the association of ORF2p with TRIM41, thereby promoting TRIM41-mediated ORF2p degradation and the suppression of L1 retrotransposition. In response to DNA damage, cGAS is phosphorylated at serine residues 120 and 305 by CHK2, which promotes cGAS-TRIM41 association, facilitating TRIM41-mediated ORF2p degradation. Moreover, we show that nuclear cGAS mediates the repression of L1 retrotransposition in senescent cells induced by DNA damage agents. We also identify several cancer-associated cGAS mutations that abolish the suppressive effect on L1 retrotransposition by disrupting the CHK2-cGAS-TRIM41-ORF2p regulatory axis. Together, these findings indicate that nuclear cGAS exhibits an inhibitory function in L1 retrotransposition which could provide avenues for future interventions in both aging and tumorigenesis. |
| first_indexed | 2024-03-08T22:37:38Z |
| format | Article |
| id | doaj.art-a5b92a9354a246c5b6f87e327ec9b427 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T22:37:38Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-a5b92a9354a246c5b6f87e327ec9b4272023-12-17T12:22:00ZengNature PortfolioNature Communications2041-17232023-12-0114111410.1038/s41467-023-43001-yNuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradationZhengyi Zhen0Yu Chen1Haiyan Wang2Huanyin Tang3Haiping Zhang4Haipeng Liu5Ying Jiang6Zhiyong Mao7Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityShanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityShanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityShanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityShanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityShanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji UniversityShanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityShanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityAbstract Cyclic GMP–AMP synthase (cGAS), initially identified as a cytosolic DNA sensor, detects DNA fragments to trigger an innate immune response. Recently, accumulating evidence reveals the presence of cGAS within the nucleus. However, the biological functions of nuclear cGAS are not fully understood. Here, we demonstrate that nuclear cGAS represses LINE-1 (L1) retrotransposition to preserve genome integrity in human cells. Mechanistically, the E3 ligase TRIM41 interacts with and ubiquitinates ORF2p to influence its stability, and cGAS enhances the association of ORF2p with TRIM41, thereby promoting TRIM41-mediated ORF2p degradation and the suppression of L1 retrotransposition. In response to DNA damage, cGAS is phosphorylated at serine residues 120 and 305 by CHK2, which promotes cGAS-TRIM41 association, facilitating TRIM41-mediated ORF2p degradation. Moreover, we show that nuclear cGAS mediates the repression of L1 retrotransposition in senescent cells induced by DNA damage agents. We also identify several cancer-associated cGAS mutations that abolish the suppressive effect on L1 retrotransposition by disrupting the CHK2-cGAS-TRIM41-ORF2p regulatory axis. Together, these findings indicate that nuclear cGAS exhibits an inhibitory function in L1 retrotransposition which could provide avenues for future interventions in both aging and tumorigenesis.https://doi.org/10.1038/s41467-023-43001-y |
| spellingShingle | Zhengyi Zhen Yu Chen Haiyan Wang Huanyin Tang Haiping Zhang Haipeng Liu Ying Jiang Zhiyong Mao Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation Nature Communications |
| title | Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation |
| title_full | Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation |
| title_fullStr | Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation |
| title_full_unstemmed | Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation |
| title_short | Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation |
| title_sort | nuclear cgas restricts l1 retrotransposition by promoting trim41 mediated orf2p ubiquitination and degradation |
| url | https://doi.org/10.1038/s41467-023-43001-y |
| work_keys_str_mv | AT zhengyizhen nuclearcgasrestrictsl1retrotranspositionbypromotingtrim41mediatedorf2pubiquitinationanddegradation AT yuchen nuclearcgasrestrictsl1retrotranspositionbypromotingtrim41mediatedorf2pubiquitinationanddegradation AT haiyanwang nuclearcgasrestrictsl1retrotranspositionbypromotingtrim41mediatedorf2pubiquitinationanddegradation AT huanyintang nuclearcgasrestrictsl1retrotranspositionbypromotingtrim41mediatedorf2pubiquitinationanddegradation AT haipingzhang nuclearcgasrestrictsl1retrotranspositionbypromotingtrim41mediatedorf2pubiquitinationanddegradation AT haipengliu nuclearcgasrestrictsl1retrotranspositionbypromotingtrim41mediatedorf2pubiquitinationanddegradation AT yingjiang nuclearcgasrestrictsl1retrotranspositionbypromotingtrim41mediatedorf2pubiquitinationanddegradation AT zhiyongmao nuclearcgasrestrictsl1retrotranspositionbypromotingtrim41mediatedorf2pubiquitinationanddegradation |