Post-translational modulation of cell signalling through protein succinylation

Abstract

Cells need toãdapt theirãctivities to extra-ãnd intracellular signalling cues. To translateã received extracellular signal, cells have specific receptors that transmit the signal to downstream proteins so that it can reach the nucleus to initiate or repress gene transcription. Post-translational modifications (PTMs) of proteinsãre reversible or irreversible chemical modifications that help to further modulate proteinãctivity. The most commonly observed PTMsãre the phosphorylation of serine, threonine,ãnd tyrosine residues, followed byãcetylation, glycosylation,ãndãmidation. Inãddition to PTMs that involve the modification ofã certainãminoãcid (phosphorylation, hydrophobic groups for membrane localisation, or chemical groups likeãcylation), or the conjugation of peptides (SUMOylation, NEDDylation), structural changes suchãs the formation of disulphide bridge, protein cleavage or splicing canãlso be classifiedãs PTMs. Recently, it was discovered that metabolites from the tricarboxylicãcid (TCA) cycleãre not only intermediates that support cellular metabolism but canãlso modify lysine residues. This has been shown forãcetate, succinate,ãnd lactate,ãmong others. Due to the importance of mitochondria for the overall fitness of organisms, the regulatory function of such PTMs is critical for protection fromãging, neurodegeneration, or cardiovascular disease. Cancer cellsãndãctivated immune cells displayã phenotype ofãccelerated metabolicãctivity knownãs the Warburg effect. This metabolic state is characterised by enhanced glycolysis, the use of the pentose phosphate pathwayãs wellãsã disruption of the TCA cycle, ultimately causing theãccumulation of metabolites like citrate, succinate,ãnd malate. Succinate can then serveãsã signalling molecule by directly interacting with proteins, by binding to its G protein-coupled receptor 91 (GPR91)ãnd by posttranslationally modifying proteins through succinylation of lysine residues, respectively. This review is focus on the process of protein succinylationãnd its importance in healthãnd disease.