Argonaute3-SF3B3 complex controls pre-mRNA splicing to restrain type 2 immunity

• DOI: 10.1016/j.celrep.2023.113515
• Publication Date: 2023-12-13T18:05:10Z
• Authors: Riccardo Guidi; Christopher Wedeles; Daqi Xu; Krzysztof Kolmus; Sarah E. Headland; Grace Teng; Joseph Guillory; Yi Jimmy Zeng; Tommy K. Cheung; Subhra Chaudhuri; Zora Modrusan; Yuxin Liang; Stuart Horswell; Benjamin Haley; Sascha Rutz; Christopher Rose; Yvonne Franke; Donald S. Kirkpat...; Jason A. Hackney; Mark S. Wilson
• Keywords: Mammals; QH301-705.5; RNA Splicing; CP: Immunology; Mice; MicroRNAs; Argonaute Proteins; RNA Precursors; Animals; CP: Molecular biology; RNA Interference; Imidazoline Receptors; RNA, Messenger; Biology (General)

Argonaute (AGO) proteins execute microRNA (miRNA)-mediated gene silencing. However, it is unclear whether all 4 mammalian AGO (AGO1, AGO2, AGO3, and AGO4) are required for miRNA activity. We generate Ago1, Ago3, Ago4-deficient mice (Ago134Δ) find AGO1/3/4 to be redundant biogenesis, homeostasis, or function, a role that carried out by AGO2. Instead, regulate the expansion of type 2 immunity via precursor mRNA splicing in CD4+ T helper (Th) lymphocytes. Gain- loss-of-function experiments demonstrate nuclear AGO3 interacts directly with SF3B3, component U2 spliceosome complex, aid global splicing, particular isoforms Nisch, resulting dysregulated Nisch isoform ratio. This work uncouples AGO1, AGO4 from miRNA-mediated RNA interference, identifies an AGO3:SF3B3 complex nucleus, reveals mechanism which inflammatory diseases.