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

Human proteins are subjected to more than 200 known post-translational modifications (PTMs) (e.g., phosphorylation, glycosylation, ubiquitination, S-nitrosylation, methylation, Nacetylation, 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.

[1]  K. Watanabe,et al.  Isolation and characterization of cDNA clones encoding rat skeletal muscle peptidylarginine deiminase. , 1989, The Journal of biological chemistry.

[2]  C. Ackerley,et al.  Peptidylarginine deiminase 2 ( PAD 2 ) overexpression in transgenic mice leads to myelin loss in the central nervous system , 2022 .

[3]  Steven Clarke,et al.  Human PAD4 Regulates Histone Arginine Methylation Levels via Demethylimination , 2004, Science.

[4]  P. Li,et al.  Coordination of PAD4 and HDAC2 in the regulation of p53-target gene expression , 2010, Oncogene.

[5]  Melissa J. Landrum,et al.  RefSeq: an update on mammalian reference sequences , 2013, Nucleic Acids Res..

[6]  C. Ackerley,et al.  Inhibition of peptidyl-arginine deiminases reverses protein-hypercitrullination and disease in mouse models of multiple sclerosis , 2012, Disease Models & Mechanisms.

[7]  Y. Akao,et al.  let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. , 2006, Biological & pharmaceutical bulletin.

[8]  P. Thompson,et al.  The protein arginine deiminases: Structure, function, inhibition, and disease. , 2013, Biopolymers.

[9]  P. Proost,et al.  Citrullination of TNF-α by peptidylarginine deiminases reduces its capacity to stimulate the production of inflammatory chemokines. , 2013, Cytokine.

[10]  I. Llewellyn-Smith,et al.  The origin of citrulline-containing proteins in the hair follicle and the chemical nature of trichohyalin, an intracellular precursor. , 1977, Biochimica et biophysica acta.

[11]  D. Dixon,et al.  The mRNA Stability Factor HuR Inhibits MicroRNA-16 Targeting of COX-2 , 2011, Molecular Cancer Research.

[12]  Pojen P. Chen,et al.  NETs Are a Source of Citrullinated Autoantigens and Stimulate Inflammatory Responses in Rheumatoid Arthritis , 2013, Science Translational Medicine.

[13]  L. Klareskog,et al.  Citrullination is an inflammation-dependent process , 2006, Annals of the rheumatic diseases.

[14]  Yuan Luo,et al.  Profiling Protein Arginine Deiminase 4 (PAD4): a novel screen to identify PAD4 inhibitors. , 2008, Bioorganic & medicinal chemistry.

[15]  Yanming Wang,et al.  Peptidylarginine deiminases in citrullination, gene regulation, health and pathogenesis. , 2013, Biochimica et biophysica acta.

[16]  A. Ishigami,et al.  cDNA cloning, gene organization and expression analysis of human peptidylarginine deiminase type I. , 2003, The Biochemical journal.

[17]  S. Coonrod,et al.  Regulation of mouse oocyte microtubule and organelle dynamics by PADI6 and the cytoplasmic lattices. , 2011, Developmental biology.

[18]  Remco Loos,et al.  Citrullination regulates pluripotency and histone H1 binding to chromatin , 2014, Nature.

[19]  P. Thompson,et al.  Potential role for PADI-mediated histone citrullination in preimplantation development , 2012, BMC Developmental Biology.

[20]  M. Moscarello,et al.  A novel microtubule independent effect of paclitaxel: the inhibition of peptidylarginine deiminase from bovine brain. , 1998, Biochimica et biophysica acta.

[21]  A. Ishida-Yamamoto,et al.  Decreased deiminated keratin K1 in psoriatic hyperproliferative epidermis. , 2000, The Journal of investigative dermatology.

[22]  George P Cobb,et al.  microRNAs as oncogenes and tumor suppressors. , 2007, Developmental biology.

[23]  L. Ware,et al.  Peptidylarginine Deiminase 2 Suppresses Inhibitory κB Kinase Activity in Lipopolysaccharide-stimulated RAW 264.7 Macrophages* , 2010, The Journal of Biological Chemistry.

[24]  R. Presland,et al.  Functional analysis of the profilaggrin N-terminal peptide: identification of domains that regulate nuclear and cytoplasmic distribution. , 2002, The Journal of investigative dermatology.

[25]  X. Chang,et al.  PADI4 and tumourigenesis , 2010, Cancer Cell International.

[26]  P. Ferretti,et al.  Modulation of calcium-induced cell death in human neural stem cells by the novel peptidylarginine deiminase–AIF pathway , 2014, Biochimica et biophysica acta.

[27]  Y. Kochi,et al.  The inhibition of antithrombin by peptidylarginine deiminase 4 may contribute to pathogenesis of rheumatoid arthritis. , 2005, Rheumatology.

[28]  G. Pruijn,et al.  Citrullination: a small change for a protein with great consequences for rheumatoid arthritis , 2000, Arthritis research.

[29]  E. Vossenaar,et al.  PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[30]  D. Peebles,et al.  Peptidylarginine deiminases: novel drug targets for prevention of neuronal damage following hypoxic ischemic insult (HI) in neonates , 2014, Journal of neurochemistry.

[31]  O. Griffith,et al.  Identification of PADI2 as a potential breast cancer biomarker and therapeutic target , 2012, BMC Cancer.

[32]  Reinout Raijmakers,et al.  Increased Citrullination of Histone H3 in Multiple Sclerosis Brain and Animal Models of Demyelination: A Role for Tumor Necrosis Factor-Induced Peptidylarginine Deiminase 4 Translocation , 2006, The Journal of Neuroscience.

[33]  A. Bruce,et al.  Mast Cells and Neutrophils Release IL-17 through Extracellular Trap Formation in Psoriasis , 2011, The Journal of Immunology.

[34]  B. Gillespie,et al.  Neutrophil Extracellular Trap–Derived Enzymes Oxidize High‐Density Lipoprotein: An Additional Proatherogenic Mechanism in Systemic Lupus Erythematosus , 2014, Arthritis & rheumatology.

[35]  W. Fast,et al.  Citrullination of Inhibitor of Growth 4 (ING4) by Peptidylarginine Deminase 4 (PAD4) Disrupts the Interaction between ING4 and p53* , 2011, The Journal of Biological Chemistry.

[36]  András Falus,et al.  Citrullination: a posttranslational modification in health and disease. , 2006, The international journal of biochemistry & cell biology.

[37]  M. Moscarello,et al.  Deimination of Human Myelin Basic Protein by a Peptidylarginine Deiminase from Bovine Brain , 1993, Journal of neurochemistry.

[38]  H. Hirano,et al.  Deimination of arginine residues in nucleophosmin/B23 and histones in HL-60 granulocytes. , 2002, Biochemical and biophysical research communications.

[39]  P. Thompson,et al.  Histone citrullination by protein arginine deiminase: is arginine methylation a green light or a roadblock? , 2006, ACS chemical biology.

[40]  M. Bedford,et al.  Discovery of peptidylarginine deiminase-4 substrates by protein array: antagonistic citrullination and methylation of human ribosomal protein S2. , 2011, Molecular bioSystems.

[41]  P. Thompson,et al.  Protein arginine deiminase 4: a target for an epigenetic cancer therapy , 2011, Cellular and Molecular Life Sciences.

[42]  W. Nauseef,et al.  Neutrophils at work , 2014, Nature Immunology.

[43]  P. Thompson,et al.  Synthesis and screening of a haloacetamidine containing library to identify PAD4 selective inhibitors. , 2012, ACS chemical biology.

[44]  T. Senshu,et al.  Preferential deimination of keratin K1 and filaggrin during the terminal differentiation of human epidermis. , 1996, Biochemical and biophysical research communications.

[45]  Guang-Yaw Liu,et al.  Vimentin Is Involved in Peptidylarginine Deiminase 2-Induced Apoptosis of Activated Jurkat Cells , 2014, Molecules and cells.

[46]  T. Katsumoto,et al.  The role of the vimentin intermediate filaments in rat 3Y1 cells elucidated by immunoelectron microscopy and computer‐graphic reconstruction , 1990, Biology of the cell.

[47]  Reinout Raijmakers,et al.  Methylation of arginine residues interferes with citrullination by peptidylarginine deiminases in vitro. , 2007, Journal of molecular biology.

[48]  Yuan Luo,et al.  The development of N-α-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-α-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine) as second generation protein arginine deiminase (PAD) inhibitors. , 2011, Journal of medicinal chemistry.

[49]  J. Norris,et al.  Autoimmunity to peptidyl arginine deiminase type 4 precedes clinical onset of rheumatoid arthritis. , 2010, Arthritis and rheumatism.

[50]  C. FordAlexander,et al.  ULCERATIVE colitis. , 1997, Journal of the American Medical Association.

[51]  R. Raijmakers,et al.  Experimental autoimmune encephalomyelitis induction in peptidylarginine deiminase 2 knockout mice , 2006, The Journal of comparative neurology.

[52]  Q. Shen,et al.  RNA aptamers interfering with nucleophosmin oligomerization induce apoptosis of cancer cells , 2009, Oncogene.

[53]  D. Wood,et al.  Rapid release and unusual stability of immunodominant peptide 45-89 from citrullinated myelin basic protein. , 1999, Biochemistry.

[54]  Toshiyuki Shimizu,et al.  Crystallization and preliminary X-ray crystallographic analysis of human peptidylarginine deiminase V. , 2003, Acta Crystallographica Section D: Biological Crystallography.

[55]  F. Mastronardi,et al.  The Role of Citrullinated Proteins Suggests a Novel Mechanism in the Pathogenesis of Multiple Sclerosis , 2006, Neurochemical Research.

[56]  T. Senshu,et al.  Deimination of 70-kD Nuclear Protein During Epidermal Apoptotic Events In Vitro , 1998, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[57]  A. Ishigami,et al.  Detection of deiminated proteins in rat skin: probing with a monospecific antibody after modification of citrulline residues. , 1995, The Journal of investigative dermatology.

[58]  A. Kawada,et al.  Molecular cloning of cDNAs of mouse peptidylarginine deiminase type I, type III and type IV, and the expression pattern of type I in mouse. , 2001, European journal of biochemistry.

[59]  P. Thompson,et al.  Kinetic characterization of protein arginine deiminase 4: a transcriptional corepressor implicated in the onset and progression of rheumatoid arthritis. , 2005, Biochemistry.

[60]  D. S. St. Clair,et al.  Nucleophosmin Blocks Mitochondrial Localization of p53 and Apoptosis* , 2009, The Journal of Biological Chemistry.

[61]  N. Greene,et al.  Protein deiminases: new players in the developmentally regulated loss of neural regenerative ability. , 2011, Developmental biology.

[62]  Deepak Poudyal,et al.  Suppression of colitis in mice by Cl-amidine: a novel peptidylarginine deiminase inhibitor. , 2011, American journal of physiology. Gastrointestinal and liver physiology.

[63]  Matthias Kretzler,et al.  Netting Neutrophils Induce Endothelial Damage, Infiltrate Tissues, and Expose Immunostimulatory Molecules in Systemic Lupus Erythematosus , 2011, The Journal of Immunology.

[64]  W. Robinson,et al.  N-α-Benzoyl-N5-(2-Chloro-1-Iminoethyl)-l-Ornithine Amide, a Protein Arginine Deiminase Inhibitor, Reduces the Severity of Murine Collagen-Induced Arthritis , 2011, The Journal of Immunology.

[65]  Jinxiang Han,et al.  Increased PADI4 expression in blood and tissues of patients with malignant tumors , 2009, BMC Cancer.

[66]  A. Ishigami,et al.  Abnormal accumulation of citrullinated proteins catalyzed by peptidylarginine deiminase in hippocampal extracts from patients with Alzheimer's disease , 2005, Journal of neuroscience research.

[67]  Yuan Luo,et al.  Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization. , 2006, Biochemistry.

[68]  J. Bilbao,et al.  Acute multiple sclerosis (marburg type) is associated with developmentally immature myelin basic protein , 1996, Annals of neurology.

[69]  A. Ishigami,et al.  Human peptidylarginine deiminase type II: molecular cloning, gene organization, and expression in human skin. , 2002, Archives of biochemistry and biophysics.

[70]  B. Garcia,et al.  Dysregulation of PAD4-mediated citrullination of nuclear GSK3β activates TGF-β signaling and induces epithelial-to-mesenchymal transition in breast cancer cells , 2013, Proceedings of the National Academy of Sciences.

[71]  V. Adoue,et al.  Peptidylarginine deiminases and deimination in biology and pathology: relevance to skin homeostasis. , 2006, Journal of dermatological science.

[72]  T. Senshu,et al.  Selective deimination of vimentin in calcium ionophore-induced apoptosis of mouse peritoneal macrophages. , 1998, Biochemical and biophysical research communications.

[73]  K. Nomura.  Specificity and mode of action of the muscle-type protein-arginine deiminase. , 1992, Archives of biochemistry and biophysics.

[74]  M. Inagaki,et al.  Ca2+-dependent deimination-induced disassembly of intermediate filaments involves specific modification of the amino-terminal head domain. , 1989, The Journal of biological chemistry.

[75]  G. Melino,et al.  Protein Unfolding by Peptidylarginine Deiminase , 1996, The Journal of Biological Chemistry.

[76]  Toshiyuki Shimizu,et al.  Structural basis for Ca2+-induced activation of human PAD4 , 2004, Nature Structural &Molecular Biology.

[77]  M. Stallcup,et al.  Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[78]  R. Denman.  PAD: the smoking gun behind arginine methylation signaling? , 2005, BioEssays : news and reviews in molecular, cellular and developmental biology.

[79]  A. Kawada,et al.  Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene, PADI6. , 2004, Gene.

[80]  C. Carmona-Rivera,et al.  Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2 , 2014, Annals of the rheumatic diseases.

[81]  Xiangli Cui,et al.  D-amino acid based protein arginine deiminase inhibitors: Synthesis, pharmacokinetics, and in cellulo efficacy. , 2012, ACS medicinal chemistry letters.

[82]  A. Nicholas,et al.  Immunohistochemical localization of citrullinated proteins in adult rat brain , 2003, The Journal of comparative neurology.

[83]  Michael J. Bolt,et al.  Peptidylarginine deiminase 2-catalyzed histone H3 arginine 26 citrullination facilitates estrogen receptor α target gene activation , 2012, Proceedings of the National Academy of Sciences.

[84]  W. V. van Venrooij,et al.  Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages , 2004, Annals of the rheumatic diseases.

[85]  L. Anguish,et al.  Potential Role for PAD2 in Gene Regulation in Breast Cancer Cells , 2012, PloS one.

[86]  P. Thompson,et al.  Substrate specificity and kinetic studies of PADs 1, 3, and 4 identify potent and selective inhibitors of protein arginine deiminase 3. , 2010, Biochemistry.

[87]  K. Watanabe,et al.  Combined biochemical and immunochemical comparison of peptidylarginine deiminases present in various tissues. , 1988, Biochimica et biophysica acta.

[88]  K. Sugawara,et al.  Properties of peptidylarginine deiminase from the epidermis of newborn rats. , 1981, Journal of biochemistry.

[89]  A. Schetter,et al.  The Induction of microRNA-16 in Colon Cancer Cells by Protein Arginine Deiminase Inhibition Causes a p53-Dependent Cell Cycle Arrest , 2013, PloS one.

[90]  Yuan Luo,et al.  A fluoroacetamidine-based inactivator of protein arginine deiminase 4: design, synthesis, and in vitro and in vivo evaluation. , 2006, Journal of the American Chemical Society.

[91]  Yusuke Nakamura,et al.  Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis , 2003, Nature Genetics.

[92]  P. Thompson,et al.  Peptidylarginine Deiminase Inhibition Reduces Vascular Damage and Modulates Innate Immune Responses in Murine Models of Atherosclerosis , 2014, Circulation research.

[93]  Y. Hidaka,et al.  Recognition of the N-terminal histone H2A and H3 peptides by peptidylarginine deiminase IV. , 2009, Protein and peptide letters.

[94]  Felipe Andrade,et al.  Peptidylarginine deiminase 2, 3 and 4 have distinct specificities against cellular substrates: novel insights into autoantigen selection in rheumatoid arthritis , 2011, Annals of the rheumatic diseases.

[95]  M. Mattson,et al.  Calcium orchestrates apoptosis , 2003, Nature Cell Biology.

[96]  R. Nagele,et al.  Neuronal PAD4 expression and protein citrullination: possible role in production of autoantibodies associated with neurodegenerative disease. , 2012, Journal of autoimmunity.

[97]  V. Adoue,et al.  Update on peptidylarginine deiminases and deimination in skin physiology and severe human diseases , 2007, International journal of cosmetic science.

[98]  H. Isomoto,et al.  Haplotypes of PADI4 susceptible to rheumatoid arthritis are also associated with ulcerative colitis in the Japanese population. , 2008, Clinical immunology.

[99]  M. Moscarello,et al.  The developmental expression and activity of peptidylarginine deiminase in the mouse , 1999, Neuroscience Letters.

[100]  Yuan Luo,et al.  Regulation of p53 Target Gene Expression by Peptidylarginine Deiminase 4 , 2008, Molecular and Cellular Biology.

[101]  P. Thompson,et al.  Protein arginine deiminase 4 (PAD4): Current understanding and future therapeutic potential. , 2009, Current opinion in drug discovery & development.

[102]  M. Rapala-Kozik,et al.  Neutrophil Extracellular Traps (nets) — Formation and Implications* , 2013 .

[103]  P. Thompson,et al.  Autodeimination of protein arginine deiminase 4 alters protein-protein interactions but not activity. , 2011, Biochemistry.

[104]  A. Ishigami,et al.  Accumulation of citrullinated proteins by up-regulated peptidylarginine deiminase 2 in brains of scrapie-infected mice: a possible role in pathogenesis. , 2008, The American journal of pathology.

[105]  Yusuke Nakamura,et al.  Regulation of histone modification and chromatin structure by the p53–PADI4 pathway , 2012, Nature Communications.

[106]  G. Rogers,et al.  Content of Citrulline and Other Amino-Acids in a Protein of Hair Follicles , 1958, Nature.