Itaconate is an anti-inflammatory metabolite that directly modifies cysteines of signaling proteins in a process called itaconation. Inflammatory cues elevate expression of the mitochondrial enzyme IRG1 and drive itaconate production from the tricarboxylic acid cycle, creating a metabolic environment that facilitates selective itaconate modification, which influences crucial anti-inflammatory and antioxidant signaling pathways, glycolysis and pyroptosis. The majority of research on itaconation has focused on intracellular reactions, and little is known about whether this modification occurs on secreted or extracellular proteins.
Now, Lu, Zhang et al. have pioneered a spatiotemporally resolved chemoproteomics workflow for post-translational modification (PTM)-based secretome profiling and used it to map secreted proteins that bear itaconate modifications. The team used the probe itaconate-alkyne (ITalk) to label itaconated proteins, followed by spintip-based affinity purification. Data-independent acquisition mass spectrometry enabled the identification of 818 macrophage-secreted proteins that had been modified by itaconation. They identified critical targets including proteins involved in lysosomes, ribosomes, glycan degradation and COVID-19, thereby expanding the known roles of itaconate across various processes of the immune system. Furthermore, the results demonstrate the functional outcome that itaconation exerts on one of its targets. In particular, itaconation of the non-receptor cytoplasmic tyrosine kinase FYN at Cys239 reduces its phosphorylation and enhances its activity.
This is a preview of subscription content, access via your institution
