cells Review Plectin in the Central Nervous System and a Putative Role in Brain Astrocytes Maja Potokar 1,2 and Jernej Jorgaˇcevski 1,2,* 1 Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia; [email protected] 2 Celica BIOMEDICAL, Tehnološki Park 24, 1000 Ljubljana, Slovenia * Correspondence: [email protected] Abstract: Plectin, a high-molecular-mass cytolinker, is abundantly expressed in the central nervous system (CNS). Currently, a limited amount of data about plectin in the CNS prevents us from seeing the complete picture of how plectin affects the functioning of the CNS as a whole. Yet, by analogy to its role in other tissues, it is anticipated that, in the CNS, plectin also functions as the key cytoskeleton interlinking molecule. Thus, it is likely involved in signalling processes, thereby affecting numerous fundamental functions in the brain and spinal cord. Versatile direct and indirect interactions of plectin with cytoskeletal filaments and enzymes in the cells of the CNS in normal physiological and in pathologic conditions remain to be fully addressed. Several pathologies of the CNS related to plectin have been discovered in patients with plectinopathies. However, in view of plectin as an integrator of a cohesive mesh of cellular proteins, it is important that the role of plectin is also considered in other CNS pathologies. This review summarizes the current knowledge of plectin in the CNS, focusing on plectin isoforms that have been detected in the CNS, along with its expression profile and distribution alongside diverse cytoskeleton filaments in CNS cell types. Considering that the bidirectional communication between neurons and glial cells, especially astrocytes, is crucial Citation: Potokar, M.; Jorgaˇcevski,J. for proper functioning of the CNS, we place particular emphasis on the known roles of plectin in Plectin in the Central Nervous neurons, and we propose possible roles of plectin in astrocytes. System and a Putative Role in Brain Astrocytes. Cells 2021, 10, 2353. Keywords: plectin; central nervous system; astrocytes; glia; neurons; intermediate filaments; micro- https://doi.org/10.3390/ tubules; actin filaments; cytolinker proteins cells10092353 Academic Editor: Bonnie Firestein 1. Plectin Received: 25 July 2021 Plectin is a large (>500 kDa) cytolinker, expressed in all mammalian tissues, and is Accepted: 7 September 2021 Published: 8 September 2021 especially abundant in epithelial and muscles cells and in the brain [1–3]. At the time of the discovery, when it was isolated as a high molecular weight polypeptide in rat glioma cell Publisher’s Note: MDPI stays neutral lysates [2], plectin was proposed to serve as a linker component between microtubules and with regard to jurisdictional claims in intermediate filaments (IFs) [1,2]. However, in time, it was revealed that plectin is much published maps and institutional affil- more than merely a physical linker connecting cytoskeleton filaments [4]. Plectin provides iations. a structural and signalling scaffold for cellular processes, ranging from cell adhesion and migration to mechanotransduction, organelle transport, and positioning, as shown in cell types of different tissues [4,5]. The versatility of plectin is rooted in its structure, which enables binding of plectin to the building proteins of the cytoskeleton. The protein has a tripartite structure, comprising Copyright: © 2021 by the authors. α Licensee MDPI, Basel, Switzerland. two large globular domains at each terminus connected by a central coiled coil of This article is an open access article helices [4]. All three domains of plectin participate in interactions with other proteins at distributed under the terms and their target sites (Figure1A). The interaction is mediated either directly or indirectly. In the conditions of the Creative Commons case of direct binding, plectin binds to all types of IFs, actin filaments and microtubules Attribution (CC BY) license (https:// (possibly through isoform-specific plectin–microtubule binding). Alternatively, indirect creativecommons.org/licenses/by/ binding of plectin is mediated by cytoskeleton-associated proteins (such as microtubule- 4.0/). associated proteins and myosin), including the building blocks of the subplasmalemmal Cells 2021, 10, 2353. https://doi.org/10.3390/cells10092353 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 18 Cells 2021, 10, 2353 2 of 17 direct binding of plectin is mediated by cytoskeleton-associated proteins (such as micro- tubule-associated proteins and myosin), including the building blocks of the subplasma- lemmalcytoskeletal cytoskeletal network, network, and other and cellular other cellul proteins,ar proteins, such as such the transmembraneas the transmembrane receptors, re- ceptors,components components of the nuclear of the envelope,nuclear envelope, and several and kinases several [3kinases–6]. Binding [3–6]. sitesBinding to different sites to differentcellular proteins cellular areproteins found are in found the conserved in the conserved parts of carboxyparts of (C)-carboxy and (C)- amino and (N)-terminal amino (N)- terminaldomains, domains, such as thesuch actin as the binding actin do-mainbinding do-main (ABD) and (ABD) plakin and domain plakin (Figuredomain1A), (Figure and 1A),are thereforeand are therefore preserved preserved across allacross plectin all plecti isoformsn isoforms [4]. Specifically, [4]. Specifically, in astrocytes in astrocytes and andneurons, neurons, ABD ABD of plectin of plectin contains contains binding binding sites for sites actin, for tubulin, actin, tubulin, IFs vimentin, IFs vimentin, and possibly and possiblysynemin synemin [4,7]. Microtubules [4,7]. Microtubul interactes interact with plectinwith plectin also indirectly,also indirectly, via theirvia their associated associ- atedproteins, proteins, MAP1, MAP1, MAP2, MAP2, and and tau attau the at plakinthe plakin domain domain [4]. [4]. Central Centralα-helical α-helical coiled-coil coiled- coilrod rod domain domain of plectin of plectin mediates mediates self-association self-association [4]. [4]. C-terminal C-terminal domain, domain, consisting consisting of sixof sixplectin plectin repeat repeat domains domains (PRD), (PRD), harbours harbours interaction interaction sites sites for for IFs IFs vimentin, vimentin, GFAP, GFAP, lamin lamin B, B,and and probably probably for for nestin nestin [3, 4[3,4,8].,8]. C-terminal C-terminal domain domain interactions interactions are extensivelyare extensively regulated regu- latedby reversible by reversible phosphorylation phosphorylation [9–11 ].[9–11]. Figure 1. Schematic representation of plectin and its transcripts generated by alternative splicing of the 5’ end of the plectin Figure 1. Schematic representation of plectin and its transcripts generated by alternative splicing of the 5’ end of the plectin gene PLEC. (A) The panel highlights interaction sites of cytoskeleton proteins and/or their associated proteins in astrocytes gene PLEC.(A) The panel highlights interaction sites of cytoskeleton proteins and/or their associated proteins in astrocytes and neurons with their respective plectin domains. The C-terminal domain consists of six plectin repeat domains (PRD). (andp), predicted neurons with interaction their respective sites of certain plectin IFs domains. with plectin The C-terminalin astrocytes domain and neuron consistss. Numbers of six plectin above repeat the schematic domains (PRD).of plectin (p), denotepredicted exons. interaction ABD, actin sites binding of certain domain. IFs with (B plectin) Transcripts in astrocytes that give and rise neurons. to indivi Numbersdual plectin above isoforms the schematic differ from of plectin each otherdenote only exons. in short ABD, sequences actin binding at the domain.5’ end of (theB) Transcriptsplectin gene. that The give numbers rise to abov individuale the schematic plectin isoformsdenote consequent differ from exons each untilother exon only 6. in Exons short sequences7 to 32 are at not the shown, 5’ endof as the they plectin are conserved gene. The among numbers isoforms above the[4]. schematic Individual denote exons consequent are indicated exons by lightuntil exonand dark 6. Exons blue 7 boxes, to 32 are representing not shown, noncoding as they are conservedand coding among regions, isoforms respecti [4].vely. Individual Red boxes exons denote are indicated two optionally by light splicedand dark exons; blue 2 boxes,α is inserted representing between noncoding exons 2 and and 3, coding while regions,3α is inserted respectively. between Red exons boxes 3 and denote 4. two optionally spliced exons; 2α is inserted between exons 2 and 3, while 3α is inserted between exons 3 and 4. The tripartite structure of plectin is preserved in all basic plectin isoforms. Namely, plectin’s first alternative exons give rise to 12 basic isoforms, which differ from each other Cells 2021, 10, 2353 3 of 17 only in the short 50-end structure of the protein (Figure1B) [ 4]. The astonishing complexity of plectin isoforms is critically important for their tissue- and cell-specific targeting [4]. The variability of plectin isoforms is further enhanced by alternative splicing of the first non-coding exons and two short exons (2α, 3α) of ABD, some of them occurring specifically in neuronal tissue [4,12,13]. Apart from variable N termini, plectin isoforms also increase their variety through the lack