Identifying Plectin Isoform Functions through Animal Models

Abstract

Plectin, a high-molecular-weight cytoskeletal linker protein, binds with high affinity to intermediate filaments of all types and connects them to junctional complexes, organelles, and inner membrane systems. In addition, it interacts with actomyosin structures and microtubules. As a multifunctional protein, plectin has been implicated in several multisystemic diseases, the most common of which is epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). A great part of our knowledge about plectin’s functional diversity has been gained through the analysis of a unique collection of transgenic mice that includes a full (null) knockout (KO), several tissue-restricted and isoform-specific KOs, three double KOs, and two knock-in lines. The key molecular features and pathological phenotypes of these mice will be discussed in this review. In summary, the analysis of the different genetic models indicated that a functional plectin is required for the proper function of striated and simple epithelia, cardiac and skeletal muscle, the neuromuscular junction, and the vascular endothelium, recapitulating the symptoms of humans carrying plectin mutations. The plectin-null line showed severe skin and muscle phenotypes reflecting the importance of plectin for hemidesmosome and sarcomere integrity; whereas the ablation of individual isoforms caused a specific phenotype in myofibers, basal keratinocytes, or neurons. Tissue-restricted ablation of plectin rendered the targeted cells less resilient to mechanical stress. Studies based on animal models other than the mouse, such as zebrafish and C. elegans, will be discussed as well.

Mutational analysis of epidermolysis bullosa in Taiwan by whole-exome sequencing complemented by RNA sequencing: a series of 77 patients

“…All seven patients with mutations in PLEC had autosomal recessive (AR) disease, with four having clinically overt muscular dystrophy. All patients with intermediate AR-EBS with muscular dystrophy had at least one mutation in exon 31 (based on NM_000445), which encodes the rod domain of PLEC [ 7 , 8 ]. One of the two patients of family 10 (PT17), who had compound heterozygous mutations (c.5269C > T and c.6067delG in PLEC) , died of respiratory infection.…”

Loss of ERβ in Aging LXRαβ Knockout Mice Leads to Colitis

“…Plectin, a cytoskeletal linker protein, binds to and interconnects intermediate filaments and attaches them to junctional complexes at the cell membrane, different organelles, and inner membrane systems. Plectin also interacts with actomyosin structures and microtubules [27]. It functions as a mediator of keratinocyte mechanical stability in the skin, primarily through linking intermediate filaments to hemidesmosomes [28].…”

Molecular Signatures Integral to Natural Reprogramming in the Pigment Epithelium Cells after Retinal Detachment in Pleurodeles waltl

“…ADAMS and ADAMTs are involved in cytokine processing and growth factor receptor shedding [51], modulate the extracellular signals, and remodel the ECM [52]. PLEC encodes a high-molecular-weight cytoskeletal linker protein plectin, which is a highly conserved and ubiquitously expressed intermediate filament-linking protein [53]. The CAPG gene (capping actin protein, gelsolinlike gene) encodes an actin regulatory protein, a member of the gelsolin/villin family of actin-regulatory proteins [54].…”