Yu Fu, Luyao Zhang, Yanjing Wang, Bo Cheng, Weiye Shi, Peiyuan Chen, Jinyu Liu, Xiaolei Zhou, Yingze Wang
{"title":"下调Tra2α和Tra2β通过调节MyD88 mRNA选择性剪接抑制巨噬细胞脂多糖诱导的炎症。","authors":"Yu Fu, Luyao Zhang, Yanjing Wang, Bo Cheng, Weiye Shi, Peiyuan Chen, Jinyu Liu, Xiaolei Zhou, Yingze Wang","doi":"10.1007/s11010-025-05394-w","DOIUrl":null,"url":null,"abstract":"<p><p>RNA binding proteins (RBPs) play a pivotal role in the posttranscriptional regulation of inflammatory processes. Transformer-2 (Tra2) is an evolutionarily conserved RBP that regulates mRNA alternative splicing, encoding two homologous proteins in vertebrates, Tra2α and Tra2β. Dysregulation of Tra2α or Tra2β may lead to the development of several inflammatory diseases. However, the roles of Tra2α and Tra2β in inflammation remain unclear. In the current research, the expression levels of Tra2α and Tra2β were upregulated in RAW264.7 macrophage cells stimulated by lipopolysaccharide (LPS). Downregulation of Tra2α or Tra2β inhibited the expression of inflammatory factors induced by LPS. Notably, combined suppression of Tra2α and Tra2β cooperatively reduced LPS-activated inflammation and suppressed the activation of NFκB and MAPK pathways. Myeloid differentiation primary response gene 88 (MyD88), a crucial adaptor in the TLR4 pathway, expresses splicing variants MyD88-L and MyD88-S, which exert pro-inflammatory and anti-inflammatory effects, respectively. We found that Tra2α and Tra2β proteins interacted with MyD88 mRNA. Moreover, downregulation of Tra2α and Tra2β promoted the expression of MyD88-S mRNA variants, thereby modulating the inflammatory response. Therefore, our findings demonstrated that Tra2α and Tra2β cooperatively regulated inflammation by modulating the alternative splicing of MyD88 in LPS-stimulated macrophages. These mechanistic insights into Tra2-mediated regulation of macrophage inflammation may provide novel therapeutic targets for treating inflammatory diseases.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Downregulation of Tra2α and Tra2β suppresses lipopolysaccharide-induced inflammation in macrophages by regulating MyD88 mRNA alternative splicing.\",\"authors\":\"Yu Fu, Luyao Zhang, Yanjing Wang, Bo Cheng, Weiye Shi, Peiyuan Chen, Jinyu Liu, Xiaolei Zhou, Yingze Wang\",\"doi\":\"10.1007/s11010-025-05394-w\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>RNA binding proteins (RBPs) play a pivotal role in the posttranscriptional regulation of inflammatory processes. Transformer-2 (Tra2) is an evolutionarily conserved RBP that regulates mRNA alternative splicing, encoding two homologous proteins in vertebrates, Tra2α and Tra2β. Dysregulation of Tra2α or Tra2β may lead to the development of several inflammatory diseases. However, the roles of Tra2α and Tra2β in inflammation remain unclear. In the current research, the expression levels of Tra2α and Tra2β were upregulated in RAW264.7 macrophage cells stimulated by lipopolysaccharide (LPS). Downregulation of Tra2α or Tra2β inhibited the expression of inflammatory factors induced by LPS. Notably, combined suppression of Tra2α and Tra2β cooperatively reduced LPS-activated inflammation and suppressed the activation of NFκB and MAPK pathways. Myeloid differentiation primary response gene 88 (MyD88), a crucial adaptor in the TLR4 pathway, expresses splicing variants MyD88-L and MyD88-S, which exert pro-inflammatory and anti-inflammatory effects, respectively. We found that Tra2α and Tra2β proteins interacted with MyD88 mRNA. Moreover, downregulation of Tra2α and Tra2β promoted the expression of MyD88-S mRNA variants, thereby modulating the inflammatory response. Therefore, our findings demonstrated that Tra2α and Tra2β cooperatively regulated inflammation by modulating the alternative splicing of MyD88 in LPS-stimulated macrophages. These mechanistic insights into Tra2-mediated regulation of macrophage inflammation may provide novel therapeutic targets for treating inflammatory diseases.</p>\",\"PeriodicalId\":18724,\"journal\":{\"name\":\"Molecular and Cellular Biochemistry\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2025-09-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular and Cellular Biochemistry\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1007/s11010-025-05394-w\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular and Cellular Biochemistry","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s11010-025-05394-w","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Downregulation of Tra2α and Tra2β suppresses lipopolysaccharide-induced inflammation in macrophages by regulating MyD88 mRNA alternative splicing.
RNA binding proteins (RBPs) play a pivotal role in the posttranscriptional regulation of inflammatory processes. Transformer-2 (Tra2) is an evolutionarily conserved RBP that regulates mRNA alternative splicing, encoding two homologous proteins in vertebrates, Tra2α and Tra2β. Dysregulation of Tra2α or Tra2β may lead to the development of several inflammatory diseases. However, the roles of Tra2α and Tra2β in inflammation remain unclear. In the current research, the expression levels of Tra2α and Tra2β were upregulated in RAW264.7 macrophage cells stimulated by lipopolysaccharide (LPS). Downregulation of Tra2α or Tra2β inhibited the expression of inflammatory factors induced by LPS. Notably, combined suppression of Tra2α and Tra2β cooperatively reduced LPS-activated inflammation and suppressed the activation of NFκB and MAPK pathways. Myeloid differentiation primary response gene 88 (MyD88), a crucial adaptor in the TLR4 pathway, expresses splicing variants MyD88-L and MyD88-S, which exert pro-inflammatory and anti-inflammatory effects, respectively. We found that Tra2α and Tra2β proteins interacted with MyD88 mRNA. Moreover, downregulation of Tra2α and Tra2β promoted the expression of MyD88-S mRNA variants, thereby modulating the inflammatory response. Therefore, our findings demonstrated that Tra2α and Tra2β cooperatively regulated inflammation by modulating the alternative splicing of MyD88 in LPS-stimulated macrophages. These mechanistic insights into Tra2-mediated regulation of macrophage inflammation may provide novel therapeutic targets for treating inflammatory diseases.
期刊介绍:
Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell.
In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.