PCBP1/2 and TDP43 Function as NAT10 Adaptors to Mediate mRNA ac4C Formation in Mammalian Cells
Abstract Massive numbers of modified bases in mRNAs sculpt the epitranscriptome and play vital roles in RNA metabolism. The only known acetylated RNA modification, N‐4‐acetylcytidine (ac4C), is highly conserved across cell types and among species. Although the GCN5‐related acetyltransferase 10 (NAT1...
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Wiley
2024-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202400133 |
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| author | Zhi‐Yan Jiang Yu‐Ke Wu Zuo‐Qi Deng Lu Chen Yi‐Min Zhu Yuan‐Song Yu Hong‐Bo Wu Heng‐Yu Fan |
| author_facet | Zhi‐Yan Jiang Yu‐Ke Wu Zuo‐Qi Deng Lu Chen Yi‐Min Zhu Yuan‐Song Yu Hong‐Bo Wu Heng‐Yu Fan |
| author_sort | Zhi‐Yan Jiang |
| collection | DOAJ |
| description | Abstract Massive numbers of modified bases in mRNAs sculpt the epitranscriptome and play vital roles in RNA metabolism. The only known acetylated RNA modification, N‐4‐acetylcytidine (ac4C), is highly conserved across cell types and among species. Although the GCN5‐related acetyltransferase 10 (NAT10) functions as an ac4C writer, the mechanism underlying the acetylation process is largely unknown. In this study, the NAT10/PCBP/TDP43 complex mediated mRNA ac4C formation in mammalian cells is identified. RNA‐binding proteins (RBPs) are identified, affiliated with two different families, poly(rC)‐binding protein 1/2 (PCBP1/2) and TAR DNA binding protein 43 (TDP43), as NAT10 adaptors for mRNA tethering and substrate selection. Knockdown of the adaptors resulted in decreased mRNA acetylation abundance in HEK293T cells and ablated cytidine‐rich ac4C motifs. The adaptors also affect the ac4C sites by recruiting NAT10 to their binding sequences. The presence of the NAT10/PCBP/TDP43 complex in mouse testes highlights its potential physiological functions in vivo. These findings reveal the composition of the mRNA ac4C writer complex in mammalian cells and expand the knowledge of mRNA acetylation and ac4C site preferences. |
| format | Article |
| id | doaj-art-99fd64ac0ab54cf8824fc1e87d318b86 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-99fd64ac0ab54cf8824fc1e87d318b862024-12-18T14:18:10ZengWileyAdvanced Science2198-38442024-12-011147n/an/a10.1002/advs.202400133PCBP1/2 and TDP43 Function as NAT10 Adaptors to Mediate mRNA ac4C Formation in Mammalian CellsZhi‐Yan Jiang0Yu‐Ke Wu1Zuo‐Qi Deng2Lu Chen3Yi‐Min Zhu4Yuan‐Song Yu5Hong‐Bo Wu6Heng‐Yu Fan7Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility Assisted Reproduction Unit Department of Obstetrics and Gynecology Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 ChinaMOE Key Laboratory for Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network Life Sciences Institute Zhejiang University Hangzhou Zhejiang 310058 ChinaMOE Key Laboratory for Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network Life Sciences Institute Zhejiang University Hangzhou Zhejiang 310058 ChinaMOE Key Laboratory for Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network Life Sciences Institute Zhejiang University Hangzhou Zhejiang 310058 ChinaDepartment of Reproductive Endocrinology, Women's Hospital, School of Medicine Zhejiang University Hangzhou 310002 ChinaSavaid Stomatology School Hangzhou Medical College Hangzhou 310053 ChinaDepartment of Reproductive Medicine Qinzhou Maternal and Child Health Care Hospital Qinzhou 535099 ChinaZhejiang Key Laboratory of Precise Protection and Promotion of Fertility Assisted Reproduction Unit Department of Obstetrics and Gynecology Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 ChinaAbstract Massive numbers of modified bases in mRNAs sculpt the epitranscriptome and play vital roles in RNA metabolism. The only known acetylated RNA modification, N‐4‐acetylcytidine (ac4C), is highly conserved across cell types and among species. Although the GCN5‐related acetyltransferase 10 (NAT10) functions as an ac4C writer, the mechanism underlying the acetylation process is largely unknown. In this study, the NAT10/PCBP/TDP43 complex mediated mRNA ac4C formation in mammalian cells is identified. RNA‐binding proteins (RBPs) are identified, affiliated with two different families, poly(rC)‐binding protein 1/2 (PCBP1/2) and TAR DNA binding protein 43 (TDP43), as NAT10 adaptors for mRNA tethering and substrate selection. Knockdown of the adaptors resulted in decreased mRNA acetylation abundance in HEK293T cells and ablated cytidine‐rich ac4C motifs. The adaptors also affect the ac4C sites by recruiting NAT10 to their binding sequences. The presence of the NAT10/PCBP/TDP43 complex in mouse testes highlights its potential physiological functions in vivo. These findings reveal the composition of the mRNA ac4C writer complex in mammalian cells and expand the knowledge of mRNA acetylation and ac4C site preferences.https://doi.org/10.1002/advs.202400133mRNA modificationN‐4‐acetylcytidineposttranscriptional regulationRNA binding proteintestistranscriptome |
| spellingShingle | Zhi‐Yan Jiang Yu‐Ke Wu Zuo‐Qi Deng Lu Chen Yi‐Min Zhu Yuan‐Song Yu Hong‐Bo Wu Heng‐Yu Fan PCBP1/2 and TDP43 Function as NAT10 Adaptors to Mediate mRNA ac4C Formation in Mammalian Cells Advanced Science mRNA modification N‐4‐acetylcytidine posttranscriptional regulation RNA binding protein testis transcriptome |
| title | PCBP1/2 and TDP43 Function as NAT10 Adaptors to Mediate mRNA ac4C Formation in Mammalian Cells |
| title_full | PCBP1/2 and TDP43 Function as NAT10 Adaptors to Mediate mRNA ac4C Formation in Mammalian Cells |
| title_fullStr | PCBP1/2 and TDP43 Function as NAT10 Adaptors to Mediate mRNA ac4C Formation in Mammalian Cells |
| title_full_unstemmed | PCBP1/2 and TDP43 Function as NAT10 Adaptors to Mediate mRNA ac4C Formation in Mammalian Cells |
| title_short | PCBP1/2 and TDP43 Function as NAT10 Adaptors to Mediate mRNA ac4C Formation in Mammalian Cells |
| title_sort | pcbp1 2 and tdp43 function as nat10 adaptors to mediate mrna ac4c formation in mammalian cells |
| topic | mRNA modification N‐4‐acetylcytidine posttranscriptional regulation RNA binding protein testis transcriptome |
| url | https://doi.org/10.1002/advs.202400133 |
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