Protein Arginine Deiminases and Associated Citrullination: Physiological Functions and Diseases Associated with Dysregulation

Abstract

Human proteins are subjected to more than 200 known post-translational modifications (PTMs) (e.g., phosphorylation, glycosylation, ubiquitination, S-nitrosylation, methylation, N-acetylation, and citrullination) and these PTMs can alter protein structure and function with consequent effects on the multitude of pathways necessary for maintaining the physiological homeostasis. When dysregulated, however, the enzymes that catalyze these PTMs can impact the genesis of countless diseases. In this review, we will focus on protein citrullination, a PTM catalyzed by the Protein Arginine Deiminase (PAD) family of enzymes. Specifically, we will describe the roles of the PADs in both normal human physiology and disease. The development of PAD inhibitors and their efficacy in a variety of autoimmune disorders and cancer will also be discussed.

Mining the Human Tissue Proteome for Protein Citrullination

“…As shown in Fig. 6B, the expression of PAD enzymes (estimated by the iBAQ approach) varied greatly between tissues consistent with earlier reports (8,48) and immunohistochemistry data available for the PAD enzymes in the Protein Atlas Project (25). For example, in brain, the expression of PAD2 is 1,000-fold higher than that of PAD4 and at least 5-fold higher than in other PAD2-expressing tissues.…”

“…Five PAD isoforms have been found in humans, PAD1-4, and the catalytically inactive PAD6 (1), which are believed to have distinct tissue-specificities (2-6). PADcatalyzed citrullination has been implicated in many cellular processes such as terminal epidermal differentiation, apoptosis, central nervous system (CNS) stability, immune response, gene regulation, and embryonic development (7,8). The modification has gained more attention recently because its pathological relevance has been established by the identification of autoantibodies recognizing citrullinated proteins in rheumatoid arthritis (RA) patients (9).…”

Peptidylarginine Deiminases—Roles in Cancer and Neurodegeneration and Possible Avenues for Therapeutic Intervention via Modulation of Exosome and Microvesicle (EMV) Release?

“…While PADs play physiological roles [39], their dysregulation is detected in various pathologies [40,41,42,43,44]. Pharmacological PAD-inhibition has shown promising results in cancer models both in vitro [45,46] and in vivo [43,47], as well as in animal models of various autoimmune diseases [48,49,50,51,52], neuronal injury [53], hypoxia [54], and atherosclerosis [55]. …”

Modulation of the cytoplasmic functions of mammalian post-transcriptional regulatory proteins by methylation and acetylation: a key layer of regulation waiting to be uncovered?

“…(2) Type I PRMTs then further modify the same nitrogen to generate asymmetrically dimethylated (aDMA) arginine, whereas (3) type II PRMTs modify the second nitrogen group to generate symmetrically dimethylated (sDMA) arginine. aDMA/sDMA PTMs were considered irreversible and could only be 'blocked' by (4) deimination to citrulline by peptidyl arginine deiminases (PADs) [95,96] but (5) PAD4 is suggested to also act on MMA to 'reverse' monobut not dimethylation. Also Jumonji domain-containing protein (JMJD) 6 catalyses (6) the conversion of aDMA, sDMA or MMA to arginine [97,98].…”