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 Kirkpatrick, Jason A Hackney, Mark S Wilson
Argonaute (AGO) proteins execute microRNA (miRNA)-mediated gene silencing. However, it is unclear whether all 4 mammalian AGO proteins (AGO1, AGO2, AGO3, and AGO4) are required for miRNA activity. We generate Ago1, Ago3, and Ago4-deficient mice (Ago134Δ ) and find AGO1/3/4 to be redundant for miRNA biogenesis, homeostasis, or function, a role that is carried out by AGO2. Instead, AGO1/3/4 regulate the expansion of type 2 immunity via precursor mRNA splicing in CD4+ T helper (Th) lymphocytes. Gain- and loss-of-function experiments demonstrate that nuclear AGO3 interacts directly with SF3B3, a component of the U2 spliceosome complex, to aid global mRNA splicing, and in particular the isoforms of the gene Nisch, resulting in a dysregulated Nisch isoform ratio...
December 26, 2023: Cell Reports