cells Review The Role of Protein Arginine Methylation as Post-Translational Modification on Actin Cytoskeletal Components in Neuronal Structure and Function Britta Qualmann * and Michael M. Kessels * Institute of Biochemistry I, Jena University Hospital—Friedrich Schiller University Jena, Nonnenplan 2-4, 07743 Jena, Germany * Correspondence: [email protected] (B.Q.); [email protected] (M.M.K.); Tel.: +49-3641-9396-300 (B.Q.); +49-3641-9396-310 (M.M.K.) Abstract: The brain encompasses a complex network of neurons with exceptionally elaborated morphologies of their axonal (signal-sending) and dendritic (signal-receiving) parts. De novo actin filament formation is one of the major driving and steering forces for the development and plasticity of the neuronal arbor. Actin filament assembly and dynamics thus require tight temporal and spatial control. Such control is particularly effective at the level of regulating actin nucleation-promoting factors, as these are key components for filament formation. Arginine methylation represents an important post-translational regulatory mechanism that had previously been mainly associated with controlling nuclear processes. We will review and discuss emerging evidence from inhibitor studies and loss-of-function models for protein arginine methyltransferases (PRMTs), both in cells and whole organisms, that unveil that protein arginine methylation mediated by PRMTs represents an important regulatory mechanism in neuritic arbor formation, as well as in dendritic spine induction, maturation Citation: Qualmann, B.; Kessels, and plasticity. Recent results furthermore demonstrated that arginine methylation regulates actin M.M. The Role of Protein Arginine cytosolic cytoskeletal components not only as indirect targets through additional signaling cascades, Methylation as Post-Translational but can also directly control an actin nucleation-promoting factor shaping neuronal cells—a key Modification on Actin Cytoskeletal process for the formation of neuronal networks in vertebrate brains. Components in Neuronal Structure and Function. Cells 2021, 10, 1079. https://doi.org/10.3390/cells10051079 Keywords: protein arginine methyltransferase (PRMT); post-translational modification; neuromor- phogenesis; actin cytoskeleton; actin nucleation; actin nucleator Cobl; arginine methylation; neuronal Academic Editors: Marco Rust and structure; dendritic spines Pirta Hotulainen Received: 25 March 2021 Accepted: 28 April 2021 1. Introduction Published: 1 May 2021 1.1. Protein Arginine Methylation Post-translational modifications are important molecular mechanisms to fine-tune Publisher’s Note: MDPI stays neutral protein structure and function, but also to reversibly and thus temporarily modulate the with regard to jurisdictional claims in activity and function of proteins. The methylation of arginine residues is catalyzed by published maps and institutional affil- protein arginine methyltransferases (PRMTs) resulting in !-NG-monomethylated arginine iations. (MMA), !-NG,NG-asymmetric dimethylarginine (ADMA) and !-NG, N’G-symmetric dimethylarginine (SDMA) (Figure1)[ 1]. Protein arginine methylation is brought about by members of the protein arginine methyltransferase family, assigned to three subfamilies according to their modes of methylation (Figures1 and2). Copyright: © 2021 by the authors. All subtypes catalyze the monomethylation of guanidino nitrogen atoms of arginine Licensee MDPI, Basel, Switzerland. residues utilizing the methyl donor S-adenosylmethionine. Additional dimethylation of This article is an open access article the monomethylated arginine is brought about solely by type I and II PRMTs, whereas distributed under the terms and the only known type III PRMT, PRMT7, solely exhibits monomethylation catalytic activity conditions of the Creative Commons because of its distinctive structural characteristics. Type I (PRMT1, PRMT2, PRMT3 and Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ PRMT4—also known as CARM1, PRMT6 and PRMT8) PRMT enzymes can additionally 4.0/). catalyze the formation of asymmetric dimethylarginine as an end-product, while type II Cells 2021, 10, 1079. https://doi.org/10.3390/cells10051079 https://www.mdpi.com/journal/cells Cells 2021, 10, x 2 of 15 Cells 2021, 10, 1079 2 of 15 PRMT4—also known as CARM1, PRMT6 and PRMT8) PRMT enzymes can additionally catalyze the formation of asymmetric dimethylarginine as an end-product, while type II PRMTs (PRMT5 and PRMT9) form in a second, subsequent step a symmetric PRMTs (PRMT5 and PRMT9) form in a second, subsequent step a symmetric dimethylargi- dimethylarginine [1,2] (Figure 1). Two potential further PRMTs, PRMT10 and PRMT11, nine [1,2] (Figure1) . Two potential further PRMTs, PRMT10 and PRMT11, have not yet have not yet been validated but were predicted to display type II PRMT activity [3]. been validated but were predicted to display type II PRMT activity [3]. PRMTs exhibit different substrate specificities, whereby a certain preference for PRMTs exhibit different substrate specificities, whereby a certain preference for glycine–arginine-richglycine–arginine-rich motifs motifs has has been been noted for some familyfamily members (PRMT1, PRMT3 andand PRMT6). PRMT6). The The substrates substrates of of PRMTs PRMTs known known thus thus far far mainly mainly play play a a role role in in chromatin- chromatin- mediatedmediated signaling signaling and and biogenesis and the maturation of ribosomes, in DNA damage responsesresponses and and in mRNA processing and transport. PRMTs PRMTs have been associated with various pathologies, particularly cancer, cancer, in inflammationflammation and immune responses [[2,4].2,4]. The rolerole ofof PRMTsPRMTs in in the the development development and and prognosis prognosis of cancer of cancer pathologies pathologies is currently is currently a major a majorfocus offocus basic of andbasic translational and translational science. science. ArginineArginine methylation methylation does does not not perturb the overall positive charge of the arginine guanidiniumguanidinium group. group. Instead, Instead, the the addition addition of of methyl groups reduces potential hydrogen bondbond interactions andand furthermorefurthermore significantlysignificantly changes changes the the shape shape and and increases increases the the size size of ofthe the modified modified arginine. arginine. Thus, Thus, arginine arginine methylation methylation mainly mainly results results in stericin steric effects effects as as well well as aschanges changes in in hydrogen hydrogen bond bond interactions interactions [5]. [5]. Figure 1. Protein Arginine Methylation by PRMTs. All three types of PRMTs (types I–III)I–III) are able to methylate one of the equivalent, terminal (!ω) nitrogen atoms (!ω-N-NG andand ω!-N’-N’GG) using) using S-adenosylmethionine S-adenosylmethionine (SAM; (SAM; AdoMet) AdoMet) as as a a methyl methyl donor. donor. The reaction leads to the generation of S-adenosylhomocysteinS-adenosylhomocystein (AdoHcys) and and monomethylarginine monomethylarginine (MMA). (MMA). TypeType III PRMTs (PRMT7) exclusively catalyze this initial step. Type Type I PRMTs (PRMT1–4, 6 and 8) can in addition methylate the already monomethylated guanidine nitrogen atom of MMA MMA fu further,rther, leading leading to to an an asymmetric asymmetric dimethylarginine dimethylarginine (ADMA). (ADMA). In contrast,contrast, typetype II II PRMTs PRMTs (PRMT5 (PRMT5 and and PRMT9) PRMT9) methylate methylate the second, the second, thusfar thus not far methylated, not meth terminalylated, terminal guanidine guanidine nitrogen nitrogen atom of MMA (ω-N’G) and thereby give rise to a symmetric dimethylarginine (SDMA). atom of MMA (!-N’G) and thereby give rise to a symmetric dimethylarginine (SDMA). 1.2.1.2. PRMTs PRMTs in the Central Nervous System AlmostAlmost 50 50 years ago, it was first first recognized that arginine-methylated proteins are abundantabundant inin brain brain extracts extracts [6]. [6]. During During the following the following decades, decades, PRMTs havePRMTs been have implicated been implicatedin the pathogenesis in the pathogenesis of different of neurological different neurological diseases, including diseases, amyotrophic including amyotrophic lateral scle- lateralrosis, glioblastomassclerosis, glioblastomas and Huntington’s and Huntington’s disease [ 1disease]. In the [1]. central In the nervouscentral nervous system system (CNS), (CNS),they have they been have attributed been attributed to functions to function in cells in maturation cell maturation and differentiationand differentiation but alsobut alsoneurodegeneration neurodegeneration [2,7, 8[2,7,8].]. Particularly, Particularly, PRMT1, PRMT1, PRMT4 PRMT4 and PRMT5 and PRMT5 have been have tightly been tightlyassociated associated with oligodendrocyte with oligodendrocyte and astroglial and astroglial maturation maturation and differentiation, and differentiation, as well as wellaxon as myelination, axon myelination, and have and been have implicated been imp inlicated neurodegenerative, in neurodegenerative, demyelinating demyelinating disease, disease,and multiple and multiple sclerosis sclerosis [9]. PRMT1 [9]. isPRMT1 essential is foressential the development for the development of neurons, of astrocytes neurons, and oligodendrocytes [8] and is required for CNS development at embryonic and perina- tal stages. CNS-specific Prmt1 knockout mice exhibited morphological abnormalities of Cells 2021, 10, x 3 of 15 Cells 2021, 10,