MHCI peptidome of HepG2 with ArgRS or SRRM2 knock down

Cells need to sense and respond adequately to environmental stimuli. Metabolites provide information on systemic changes, for example during inflammation. We show that depletion of the amino acid arginine during inflammation reduced nuclear levels of its cognate aminoacyl tRNA synthetase, Arginyl-tRNA synthetase (ArgRS). In the nucleus, ArgRS interacted with serine/arginine repetitive matrix protein 2 (SRRM2), a spliceosomal protein and nuclear speckle organizer, in distinct condensate-like structures. ArgRS’ presence in the nucleus impeded SRRM2 mobility. Differences in SRRM2 speckle trafficking were directly reflected in alternative mRNA splicing: splice site usage was regulated in the opposite direction by ArgRS as by SRRM2, suggesting sequestration of SRRM2 by ArgRS as a regulatory mechanism. ArgRS- and SRRM2-dependent mRNA processing changes cumulated in altered metabolism and peptide presentation to immune cells. Our findings indicate a general mechanism in which ArgRS and SRRM2 act together as upstream regulators during the physiological response to inflammatory injury.