An Overview of the Intrinsic Role of Citrullination in Autoimmune Disorders

Abstract

A protein undergoes many types of posttranslation modification. Citrullination is one of these modifications, where an arginine amino acid is converted to a citrulline amino acid. This process depends on catalytic enzymes such as peptidylarginine deiminase enzymes (PADs). This modification leads to a charge shift, which affects the protein structure, protein-protein interactions, and hydrogen bond formation, and it may cause protein denaturation. The irreversible citrullination reaction is not limited to a specific protein, cell, or tissue. It can target a wide range of proteins in the cell membrane, cytoplasm, nucleus, and mitochondria. Citrullination is a normal reaction during cell death. Apoptosis is normally accompanied with a clearance process via scavenger cells. A defect in the clearance system either in terms of efficiency or capacity may occur due to massive cell death, which may result in the accumulation and leakage of PAD enzymes and the citrullinated peptide from the necrotized cell which could be recognized by the immune system, where the immunological tolerance will be avoided and the autoimmune disorders will be subsequently triggered. The induction of autoimmune responses, autoantibody production, and cytokines involved in the major autoimmune diseases will be discussed.

Post-Translational Protein Deimination Signatures in Serum and Serum-Extracellular Vesicles of Bos taurus Reveal Immune, Anti-Pathogenic, Anti-Viral, Metabolic and Cancer-Related Pathways for Deimination

“…Calcium is a key modulator in a range of immunological, metabolic and developmental functions [199][200][201][202]. Calcium signalling is linked to a wide range of physiological and pathological processes [203][204][205], is a key driver for post-translational deimination [206][207][208] and plays an important role in the regulation of EVs [11,48]. In cattle, calcium is linked to many immunological pathways including inflammatory diseases [209], virus replication [210], parasitic infection [211], wound healing [212], reproduction [213,214] and adrenal function [215].…”

Autophagy in Multiple Sclerosis: Two Sides of the Same Coin

“…Citrullination is a posttranslational modification that converts arginine into citrulline, this conversion is relevant for antigen presentation because it generates neo-epitopes that can be recognized by the immune system (Guan et al, 2019). Autophagy is responsible for the generation and processing of citrullinated peptides (Ireland and Unanue, 2011;Münz, 2016;Morandi et al, 2017), resulting in neo-epitopes that could be recognized by T-cells and induce an autoimmune response (Alghamdi et al, 2019). An interesting finding has been that the processing of citrullinated peptides depends on autophagy induction in B-cells, whereas unmodified peptides are unaffected when autophagy was blocked in this cell type with 3methyladenine (Ireland and Unanue, 2011).…”

Peptidyl Arginine Deiminase 2 (PADI2)-Mediated Arginine Citrullination Modulates Transcription in Cancer

“…Additional evidence that citrullination affects the functional protein-protein interactions derives from observation in macrophage differentiation, where citrullination of plasminogen activator inhibitor-2 inhibits its binding ability to proteasome subunit beta type-1 to then modulate the inflammatory response [12]. Changes in citrullination occur in several pathological conditions such as autoimmune disorders and chronic inflammation-related diseases, including periodontitis, rheumatoid arthritis, atherosclerosis, and diabetes [13][14][15] (see Alghamdi, M. et al [13] for a detailed review on the intrinsic role of citrullination in autoimmune disorders and Olsen, I. et al, [14] for a detailed review on citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis, and Alzheimer's disease). Altered levels of citrullination have also been shown in neurological disorders and prion diseases, [16,17] and respiratory disorders [18,19].…”