Arg-tRNA synthetase links inflammatory metabolism to RNA splicing and nuclear trafficking via SRRM2

Nat Cell Biol. 2023 Apr;25(4):592-603. doi: 10.1038/s41556-023-01118-8. Epub 2023 Apr 14.


Cells respond to perturbations such as inflammation by sensing changes in metabolite levels. Especially prominent is arginine, which has known connections to the inflammatory response. Aminoacyl-tRNA synthetases, enzymes that catalyse the first step of protein synthesis, can also mediate cell signalling. Here we show that depletion of arginine during inflammation decreased levels of nuclear-localized arginyl-tRNA synthetase (ArgRS). Surprisingly, we found that nuclear ArgRS interacts and co-localizes with serine/arginine repetitive matrix protein 2 (SRRM2), a spliceosomal and nuclear speckle protein, and that decreased levels of nuclear ArgRS correlated with changes in condensate-like nuclear trafficking of SRRM2 and splice-site usage in certain genes. These splice-site usage changes cumulated in the synthesis of different protein isoforms that altered cellular metabolism and peptide presentation to immune cells. Our findings uncover a mechanism whereby an aminoacyl-tRNA synthetase cognate to a key amino acid that is metabolically controlled during inflammation modulates the splicing machinery.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism
  • Amino Acyl-tRNA Synthetases* / genetics
  • Amino Acyl-tRNA Synthetases* / metabolism
  • Arginine / chemistry
  • Arginine / genetics
  • Arginine / metabolism
  • Arginine-tRNA Ligase* / chemistry
  • Arginine-tRNA Ligase* / genetics
  • Arginine-tRNA Ligase* / metabolism
  • RNA Splicing
  • RNA-Binding Proteins / metabolism


  • Amino Acids
  • Amino Acyl-tRNA Synthetases
  • Arginine
  • Arginine-tRNA Ligase
  • RNA-Binding Proteins