Mediated Arginine Citrullination Modulates Transcription in Cancer
Total Page：16
File Type：pdf, Size：1020Kb
International Journal of Molecular Sciences Review Peptidyl Arginine Deiminase 2 (PADI2)-Mediated Arginine Citrullination Modulates Transcription in Cancer Miguel Beato 1,2,* and Priyanka Sharma 1,* 1 Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain 2 Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain * Correspondence: [email protected] (M.B.); [email protected] (P.S.) Received: 17 January 2020; Accepted: 11 February 2020; Published: 17 February 2020 Abstract: Protein arginine deimination leading to the non-coded amino acid citrulline remains a key question in the field of post-translational modifications ever since its discovery by Rogers and Simmonds in 1958. Citrullination is catalyzed by a family of enzymes called peptidyl arginine deiminases (PADIs). Initially, increased citrullination was associated with autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, as well as other neurological disorders and multiple types of cancer. During the last decade, research efforts have focused on how citrullination contributes to disease pathogenesis by modulating epigenetic events, pluripotency, immunity and transcriptional regulation. However, our knowledge regarding the functional implications of citrullination remains quite limited, so we still do not completely understand its role in physiological and pathological conditions. Here, we review the recently discovered functions of PADI2-mediated citrullination of the C-terminal domain of RNA polymerase II in transcriptional regulation in breast cancer cells and the proposed mechanisms to reshape the transcription regulatory network that promotes cancer progression. Keywords: arginine citrullination; RNA polymerase II; transcription; pause release; cell proliferation; P-TEFb complex; histone H3; chromatin; phase separation; cancer 1. Introduction Deimination or citrullination as first described in 1958 by Rogers and Simmonds is a post-translational conversion of peptidyl-arginine to non-coded peptidyl-citrulline catalyzed by Ca2+- dependent peptidyl arginine deiminase (PADI) enzymes [1–4]. Citrullination produces a loss of a positive charge, which increases the mass by 0.984 Da [5], and the acidity of the amino acid side chain, as the iso-electric point (pI) changes from 11.41 for arginine to 5.91 for citrulline [6]. Studies in human embryonic kidney (HEK-293) cells found hundreds of proteins that can undergo citrullination, in which 25% of total citrullinated sites contained arginine-glycine-glycine (RGG)/arginine-glycine (RG) binding motifs [7]. These results highlighted that RNA-binding proteins can undergo citrullination to modulate the RNA processing. Citrullination also increases the hydrophobicity and conformation of proteins, which can potentially affect hydrogen bond formation, protein structure, protein-protein interactions and protein-nucleic acid interactions [7–9]. Given the significance of these interactions for essential cellular functions, citrullination may uniquely modulate cellular processes (Figure1). The transformation in protein complexes can change the half-life, stability, and also expose proteins to degradation. For example, citrullination of filament aggregating protein that binds to keratin fibers in epithelial cells (filaggrin) leads to the partial unfolding of this protein, decreases their affinity for keratins, Int. J. Mol. Sci. 2020, 21, 1351; doi:10.3390/ijms21041351 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 1351 2 of 16 and,Int.thereby, J. Mol. Sci. makes2020, 21, 1351 it more prone to degradation by several proteases including caspase 142 [ 10of 16,11 ]. Additional evidence that citrullination affects the functional protein-protein interactions derives from observation[10,11]. Additional in macrophage evidence diff thaterentiation, citrullination where affects citrullination the function of plasminogenal protein-protein activator interaction inhibitor-2s inhibitsderives its from binding observ abilityation to in proteasome macrophage subunit differentiation beta type-1, where to then citrullination modulate of the p inflammatorylasminogen responseactivator [12 inhibitor]. -2 inhibits its binding ability to proteasome subunit beta type-1 to then modulate the inflammatory response [12]. Figure 1. Arginine citrullination and its cellular functions. (A) The peptidyl arginine deiminases (PADI) enzyme catalyze peptidyl-arginine (positively charged) to peptidyl-citrulline (neutral in charge) and release of ammonia. (B) Arginine (green) to citrulline (orange) conversion could consequently affects Figure 1. Arginine citrullination and its cellular functions. (A) The peptidyl arginine deiminases the functional protein-protein and protein-nucleic acid interactions by affecting the protein folding, (PADI) enzyme catalyze peptidyl-arginine (positively charged) to peptidyl-citrulline (neutral in as well as intermolecular and intramolecular interactions. “+” and “ ” signs representing the positive charge) and release of ammonia. (B) Arginine (green) to citrulline− (orange) conversion could and negative interactions respectively. consequently affects the functional protein-protein and protein-nucleic acid interactions by affecting the protein folding, as well as intermolecular and intramolecular interactions. “+” and “−” signs Changes in citrullination occur in several pathological conditions such as autoimmune representing the positive and negative interactions respectively. disorders and chronic inflammation-related diseases, including periodontitis, rheumatoid arthritis, atherosclerosis,Changes andin citrullination diabetes [13 occur–15] (seein several Alghamdi, pathological M. et al. conditions [13] for a such detailed as autoimmune review on thedisorders intrinsic roleand of citrullinationchronic inflammation in autoimmune-related disordersdiseases, andincluding Olsen, I.periodontitis et al., [14], forrheumatoid a detailed reviewarthritis, on citrullinationatherosclerosis as a, plausibleand diabetes link [13 to– periodontitis,15] (see Alghamdi rheumatoid, M. et al. arthritis,[13] for a atherosclerosis,detailed review on and the Alzheimer’s intrinsic disease).role of Alteredcitrullination levels in of autoimmune citrullination disorders have also and been Olsen shown, I. et in al., neurological [14] for a detailed disorders review and prionon diseases,citrullination [16,17] andas a respiratory plausible disorderslink to periodontitis [18,19]. Citrullination, rheumatoid can generatearthritis, new atherosclerosis epitopes, which, and can produceAlzheimer new’s autoantigens disease). Altered linked level tos altered of citrullination immune have responses also been (see shown [20] for in a neurologic review onal citrullination disorders andand autoimmunity). prion diseases The, [16,17 citrullination] and respiratory of histones disorders in neutrophils [18,19 facilitates]. Citrullination neutrophil can extracellulargenerate new trap (NET)epitopes formation, which or can NETosis, produce which new is autoantigen implicated ins linked innate to immune altered responses immune response ([21]; sees [ 22(see] for [20 a] detailed for a reviewreview on on citrullination citrullination and and NET).autoimmunity Remarkably,). The citrullination-directedcitrullination of histones chromatin in neutrophils decondensation facilitates leadsneutrophil to transcriptional extracellular firing trap in (NET) neutrophils formation that facilitatesor NETosis NET, which formation is implicated [23]. Moreover, in innate recent immune work demonstratedresponses ([21 that]; see citrullination [22] for a detailed in macrophages review on citrullination induced inflammatory and NET). Remarkably processes or, citrullination the pyroptotic- formdirected of cell chromatin death, which decondensation is required for leads inflammasome to transcriptional assembly firing and in neutrophils proinflammatory that facilitate interleukin-1s NET β formation [23]. Moreover, recent work demonstrated that citrullination in macrophages induced (IL-1β) release [24]. Moreover, citrullination contributes to cancer progression. Recent research seeks inflammatory processes or the pyroptotic form of cell death, which is required for inflammasome to elucidate how citrullination of several essential proteins drives multiple disease conditions. In this assembly and proinflammatory interleukin-1IL-1release [24]. Moreover, citrullination review, we focus on the role of PADI2-mediated arginine citrullination and their functional impact on contributes to cancer progression. Recent research seeks to elucidate how citrullination of several transcriptional regulation and cancer progression. essential proteins drives multiple disease conditions. In this review, we focus on the role of PADI2- 2. Functionalmediated arginine Role of citrullination PADI Family and their functional impact on transcriptional regulation and cancer progression. Rogers and Taylor [25] discovered a previously unidentified enzymatic activity when generating peptidyl-citrulline2. Functional Role in of hair PADI follicle Family extracts in 1977. The responsible enzymes were later identified as peptidylRogers arginine and deiminasesTaylor [25] discovered (PADI). The a previouslyPADI family unidentified is a group enzymatic of five calcium-dependent activity when generating enzymes, peptidyl-citrulline in hair follicle extracts in 1977. The responsible enzymes were later identified as Int. J.