Citrullination in the pathology of inflammatory and autoimmune disorders: recent advances and future perspectives

Abstract

Numerous post-translational modifications (PTMs) govern the collective metabolism of a cell through altering the structure and functions of proteins. The action of the most prevalent PTMs, encompassing phosphorylation, methylation, acylations, ubiquitination and glycosylation is well documented. A less explored protein PTM, conversion of peptidylarginine to citrulline, is the subject of this review. The process of citrullination is catalysed by peptidylarginine deiminases (PADs), a family of conserved enzymes expressed in a variety of human tissues. Accumulating evidence suggest that citrullination plays a significant role in regulating cellular metabolism and gene expression by affecting a multitude of pathways and modulating the chromatin status. Here, we will discuss the biochemical nature of arginine citrullination, the enzymatic machinery behind it and also provide information on the pathological consequences of citrullination in the development of inflammatory diseases (rheumatoid arthritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, periodontitis and COVID-19), cancer and thromboembolism. Finally, developments on inhibitors against protein citrullination and recent clinical trials providing a promising therapeutic approach to inflammatory disease by targeting citrullination are discussed.

Peritoneal autoantibody landscape in endometriosis

“…Citrullination is a post-translational modification by which arginine is converted to citrulline by peptidylarginine deiminases (PADs) unveiling novel antigenic epitopes that are over-enriched in several autoimmune diseases 55 . For the study of citrullinated targets, we pooled PF samples from EM+ patients based on their levels of anti-p53 AAb into two anti-p53 AAb groups (p53 high and p53 low ) ( Figure 3A ).…”

“…This study showed that women with endometriosis have native and citrullinated anti-p53 AAbs, among others. To date, five human PAD isotypes that are responsible for enzymatically modifying arginine to citrulline have been described 55 . PAD1 is expressed mainly in the uterus, PAD2 have widespread distribution including expression in the uterus, PAD3 is found in the epidermis, PAD4 expression is mainly restricted to leukocytes and PAD6 is expressed in ovaries and is a crucial enzyme in fertility 40,41,90,91 .…”

Unique Posttranslational Modification Sites of Acetylation, Citrullination, Glutarylation, and Phosphorylation Are Found to Be Specific to the Proteins Partitioned in the Triton X-114 Fractions of Leptospira

“… 25 − 27 Further, new evidence suggests that citrullination can play a significant role in regulating gene expression and cellular metabolism. 28 Though citrullination was not reported earlier in Leptospira , 5667 deamidations of asparagine and glutamine as dynamic modifications are available in the supplementary files of the proteomic analysis work on Leptospira biflexa . 14 Another PTM associated to a greater degree with the aqueous fraction was acetylation, which is higher in aqueous.…”

The virtues and vices of protein citrullination

“…NETosis constitutes a fast and effective response to infection, however, the deregulation of this process and associated release of inflammatory cytokines, proteases and active PADIs to the extracellular space, are highly destructive for the surrounding tissue and have been associated with the exacerbation of a remarkable array of pathologies, including RA, lupus erythematosus, ulcerative colitis, inflammatory bowel disease, atherosclerosis, sepsis, type I diabetes and severe Covid-19 (reviewed recently in detail in [ 125 ]) ( figure 2 ).…”