Implications of Post-Translational Modifications in Autoimmunity with Emphasis on Citrullination, Homocitrullination and Acetylation for the Pathogenesis, Diagnosis and Prognosis of Rheumatoid Arthritis

Abstract

Post-translational modifications (PTMs) influence cellular processes and consequently, their dysregulation is related to the etiologies of numerous diseases. It is widely known that a variety of autoimmune responses in human diseases depend on PTMs of self-proteins. In this review we summarize the latest findings about the role of PTMs in the generation of autoimmunity and, specifically, we address the most relevant PTMs in rheumatic diseases that occur in synovial tissue. Citrullination, homocitrullination (carbamylation) and acetylation are responsible for the generation of Anti-Modified Protein/Peptide Antibodies (AMPAs family), autoantibodies which have been implicated in the etiopathogenesis, diagnosis and prognosis of rheumatoid arthritis (RA). Synthetic peptides provide complete control over the exact epitopes presented as well as the specific positions in their sequence where post-translationally modified amino acids are located and are key to advancing the detection of serological RA biomarkers that could be useful to stratify RA patients in order to pursue a personalized rheumatology. In this review we specifically address the latest findings regarding synthetic peptides post-translationally modified for the specific detection of autoantibodies in RA patients.

Keywords: ACPA; AMPA; acetylation; citrullination; homocitrullination; post-translational modification; rheumatoid arthritis; synthetic peptides.

Figure 1

Natural and modified structures of amino acids that undergo the most frequent PTMs. His phosphorylation is understudied compared to that of Ser, Thr or Tyr.

Figure 2

Relevant PTMs in inflammatory rheumatic diseases.

Figure 3

Scheme of cyclic chimeric citrullinated peptides derived from different proteins present in the rheumatoid synovial fluid. The protein domains and the citrullination positions are indicated for each cyclic chimeric peptide.

Figure 4

Primary structure of cyclic chimeric peptides bearing one, two and three PTMs in their sequence. Cit: citrulline; hCit: homocitrulline; KAc: acetyl-lysine.