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

Cell Rep. 2023 Dec 26;42(12):113515. doi: 10.1016/j.celrep.2023.113515. Epub 2023 Dec 13.

Abstract

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. This work uncouples AGO1, AGO3, and AGO4 from miRNA-mediated RNA interference, identifies an AGO3:SF3B3 complex in the nucleus, and reveals a mechanism by which AGO proteins regulate inflammatory diseases.

Keywords: CP: Immunology; CP: Molecular biology; IL-13; RNAi; T cell; T(H)2; allergy; eosinophil; gene regulation; helminth; lymphocyte; miRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Argonaute Proteins / genetics
  • Argonaute Proteins / metabolism
  • Imidazoline Receptors / genetics
  • Imidazoline Receptors / metabolism
  • Mammals / metabolism
  • Mice
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • RNA Interference
  • RNA Precursors* / genetics
  • RNA Precursors* / metabolism
  • RNA Splicing / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism

Substances

  • Argonaute Proteins
  • Imidazoline Receptors
  • MicroRNAs
  • Nisch protein, mouse
  • RNA Precursors
  • RNA, Messenger
  • Ago3 protein, mouse
  • Sf3b3 protein, mouse