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A Reporter Based Cellular Assay for Monitoring Splicing Efficiency
Published on: September 15, 2021
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Argonaute3-SF3B3 complex controls pre-mRNA splicing to restrain type 2 immunity
Riccardo Guidi1, Christopher Wedeles1, Daqi Xu1
1Immunology Discovery, Genentech, South San Francisco, CA 94080, USA.
Cell Reports
|December 14, 2023
Summary
Argonaute proteins AGO1, AGO3, and AGO4 are not essential for microRNA function but regulate T helper cell immunity through mRNA splicing. They interact with the spliceosome to control gene expression and inflammatory responses.
Area of Science:
- Molecular Biology
- Immunology
- Genetics
Background:
- Argonaute (AGO) proteins are key mediators of microRNA (miRNA)-guided gene silencing.
- The specific roles of all four mammalian AGO proteins (AGO1-4) in miRNA activity and other cellular processes remain incompletely understood.
Purpose of the Study:
- To investigate the distinct functions of AGO proteins beyond canonical miRNA-mediated gene silencing.
- To determine the requirement of AGO1, AGO3, and AGO4 in miRNA activity and immune cell function.
Main Methods:
- Generation and analysis of Ago1, Ago3, and Ago4-deficient mice (Ago134Δ).
- Gain- and loss-of-function experiments in CD4+ T helper lymphocytes.
- Co-immunoprecipitation assays to identify protein interactions.
Main Results:
- AGO1, AGO3, and AGO4 are redundant for miRNA biogenesis and function, with AGO2 fulfilling this role.
- AGO1/3/4 are crucial for regulating type 2 immunity expansion through precursor mRNA splicing in CD4+ T helper cells.
- Nuclear AGO3 directly interacts with SF3B3, a spliceosome component, to regulate global mRNA splicing and Nisch gene isoforms.
Conclusions:
- AGO1, AGO3, and AGO4 are uncoupled from miRNA-mediated RNA interference.
- A novel AGO3:SF3B3 nuclear complex involved in mRNA splicing and immune regulation is identified.
- This study reveals a new mechanism for AGO protein involvement in inflammatory diseases through spliceosome modulation.
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