cells Review Plectin-Mediated Intermediate Filament Functions: Why Isoforms Matter Gerhard Wiche Max Perutz Laboratories, Department of Biochemistry and Cell Biology, University of Vienna, 1030 Vienna, Austria; [email protected] Abstract: This essay focuses on the role of plectin and its various isoforms in mediating intermedi- ate filament (IF) network functions. It is based on previous studies that provided comprehensive evidence for a concept where plectin acts as an IF recruiter, and plectin-mediated IF networking and anchoring are key elements in IF function execution. Here, plectin’s global role as modulator of IF functionality is viewed from different perspectives, including the mechanical stabilization of IF networks and their docking platforms, contribution to cellular viscoelasticity and mechan- otransduction, compartmentalization and control of the actomyosin machinery, connections to the microtubule system, and mechanisms and specificity of isoform targeting. Arguments for IF net- works and plectin acting as mutually dependent partners are also given. Lastly, a working model is presented that describes a unifying mechanism underlying how plectin–IF networks mechanically control and propagate actomyosin-generated forces, affect microtubule dynamics, and contribute to mechanotransduction. Keywords: plectin; isoforms; intermediate filaments; mechanotransduction; actomyosin; microtubules Citation: Wiche, G. Plectin-Mediated 1. Introduction Intermediate Filament Functions: Why Isoforms Matter. Cells 2021, 10, Plectin, a cytolinker protein and member of the plakin protein family [1], was described 2154. https://doi.org/10.3390/ and first characterized some 40 years ago [2]. The protein was shown to play a central cells10082154 role in the organization and performance of the vertebrate cell cytoskeleton. Not only is it essential for the functionality of intermediate filament (IF) networks of different types, Academic Editor: Rudolf E. Leube but it also affects the dynamic behavior and site of action of the contractile and polarizing actomyosin and microtubule (MT) network systems [3–6]. With a polypeptide chain length Received: 3 August 2021 of ~4500 amino-acid residues, plectin is a huge multidomain protein, comprising a variable Accepted: 17 August 2021 N terminus, followed by a classical actin-binding domain (ABD) and a plakin domain, Published: 21 August 2021 a central helical rod domain, and a long C-terminal domain [5]. The ABD comprises a pair of calponin homology (CH) domains, and the plakin domain contains nine spectrin Publisher’s Note: MDPI stays neutral repeats with an SH3 domain embedded within the fifth repeat [7]. Via their central α-helical with regard to jurisdictional claims in domain, plectin molecules dimerize to form a ~200 nm long rod of a coiled-coil helical published maps and institutional affil- structure; the lateral association of rod domains leads to plectin oligomers. The C-terminal iations. domain is built up of six plectin repeat domains (PRDs) of roughly 300 residues each, separated by linker regions of variable sizes, and a short C-terminal tail. Within each PRD lies a highly conserved central core, and within the linker region between PRDs 5 and 6 resides plectin’s major IF-binding domain (IFBD) [8]. Copyright: © 2021 by the author. What makes plectin quite unique is its isoform diversity based on multiple variable Licensee MDPI, Basel, Switzerland. first exons alternatively splicing into a common exon 2, generating a hydra-like pattern This article is an open access article of alternative transcripts. There are about a dozen of such transcripts, sharing a common distributed under the terms and structure composed of over 30 exons, but differing from each other by their very N-terminal conditions of the Creative Commons head domains. Additional alternative splicing of small exons into plectin’s ABD and of Attribution (CC BY) license (https:// a single large exon (exon 31) encoding the entire α-helical coiled-coil rod domain of the creativecommons.org/licenses/by/ molecule gives rise to a multiplicity of plectin variants [9]. The isoforms encoded by 4.0/). Cells 2021, 10, 2154. https://doi.org/10.3390/cells10082154 https://www.mdpi.com/journal/cells Cells 2021, 10, 2154 2 of 21 of a single large exon (exon 31) encoding the entire α-helical coiled-coil rod domain of the Cells 2021, 10, 2154 molecule gives rise to a multiplicity of plectin variants [9]. The isoforms encoded2 ofby 21 these transcript variants were named according to their alternative first coding exons in chron- ological order of their identification. Accordingly, the first isoform identified was given thethese name transcript plectin isoform variants were1 (P1), named followed according by isoforms to their alternativeP1a, P1b, P1c, first codingetc., with exons P1k in being thechronological last isoform orderidentified of their (for identification. a more detailed Accordingly, description the of first isoforms isoform and identified corresponding was transcriptgiven the variants, name plectin see [5]). isoform 1 (P1), followed by isoforms P1a, P1b, P1c, etc., with P1kAs being shown the by last expression isoform identified profiling, (for different a more detailedtypes of description cells and tissues of isoforms express and these corresponding transcript variants, see [5]). isoforms in different combinations and proportions, often in dependence of their devel- As shown by expression profiling, different types of cells and tissues express these opmentalisoforms stage in different [10,11]. combinations The observation and proportions, of distinct oftenisoform in dependence expression ofpatterns their devel- has been theopmental basis for stagea working [10,11]. model The observation where the of expression distinct isoform of different expression sets patterns of plectin has isoforms been is tailoredthe basis for forparticular a working functional model where needs the of expression the cell, ofin differenta kind of sets “custom of plectin-made” isoforms fashion. Importantis tailored for for the particular understanding functional of needs plectin’s of the multiple cell, in a functions kind of “custom-made” was the observation fashion. that theImportant various isoform for the understanding-specific N-terminal of plectin’s head multiple domains functions dictate was the the cellular observation localization that of thethe isoform various [12], isoform-specific by dockingN to-terminal distinct head interaction domains partners. dictate the A cellular few isoform localization-specific of the inter- actionisoform partners [12], by have docking indeed to distinct been identified; interaction however, partners. A in few several isoform-specific other cases, interaction isoform-spe- partners have indeed been identified; however, in several other cases, isoform-specific cific interaction partners and targeting mechanisms are still unknown. As all the isoforms interaction partners and targeting mechanisms are still unknown. As all the isoforms are areendowed endowed with with a universala universal high high affinity affinity IF-binding IF-binding domain domain at their at theirC termini, C termini, they willthey will recruitrecruit and and anchor anchor IF IF networks networks ofof anyany type type to to the the various various sites sites and and structures structures with with which which theythey are are associated. associated. This This is anan important important concept, concept, as itas leads it leads to an to isoform-dependent an isoform-dependent inter- in- terlinkinglinking ofof different different cellular cellular structures structures and and organelles organelles via IFs, via with IFs, major with implications major implications for forcytoarchitecture, cytoarchitecture, shape, shape, polarization, polarization, and migrationand migration potential potential of cells [of4– 6cells,13]; [4 see–6,13]; Figure see1 Fig- urefor 1 for a schematic a schematic drawing drawing of the of plectin the plectin molecule molecule and its diverseand its head diverse domains). head domains). FigureFigure 1. Schematic 1. Schematic representation representation of ofa plectin a plectin dimer. dimer. The The NN--terminalterminal domain domain contains contains two two actin-binding actin-binding domains domains (ABDs) (ABDs) each consistingeach consisting of two of two calponin calponin homology homology domains domains (light (light and darkdark red),red), and and two two plakin plakin domains domains each each comprising comprising nine nine spectrinspectrin repeats repeats (green) (green) and and one one (noncanonical) (noncanonical) SH3 SH3 domain domain (yellow).(yellow). The The central central coiled-coil coiled-coil rod rod domain domain is ~200 is ~200 nm long. nm long. The CThe-terminalC-terminal domains domains each each contain contain six six plectin repeat repeat domains domains (PRDs), (PRDs), where where PRDs PRDs consist consist of a conserved of a conserved region, referred region, re- ferredto to as as module, module, and and a linker a linker region, region, one of one which of which harbors harbors the universal the universal IF-binding IF domain-binding (IFBD). domain The (IFBD). stars at theTheN starstermini at the N terminiof theof the polypeptide polypeptide chains chains stand forstand the differentfor the different isoform-specific isoform head-specific domains. head Nine domains. alternative Nine head alternative domains are head depicted domains are depicted(color-coded (color bars),-coded giving bars), the namegiving