Plastin 3 in health and disease: a matter of balance

Abstract

For a long time, PLS3 (plastin 3, also known as T-plastin or fimbrin) has been considered a rather inconspicuous protein, involved in F-actin-binding and -bundling. However, in recent years, a plethora of discoveries have turned PLS3 into a highly interesting protein involved in many cellular processes, signaling pathways, and diseases. PLS3 is localized on the X-chromosome, but shows sex-specific, inter-individual and tissue-specific expression variability pointing towards skewed X-inactivation. PLS3 is expressed in all solid tissues but usually not in hematopoietic cells. When escaping X-inactivation, PLS3 triggers a plethora of different types of cancers. Elevated PLS3 levels are considered a prognostic biomarker for cancer and refractory response to therapies. When it is knocked out or mutated in humans and mice, it causes osteoporosis with bone fractures; it is the only protein involved in actin dynamics responsible for osteoporosis. Instead, when PLS3 is upregulated, it acts as a highly protective SMN-independent modifier in spinal muscular atrophy (SMA). Here, it seems to counteract reduced F-actin levels by restoring impaired endocytosis and disturbed calcium homeostasis caused by reduced SMN levels. In contrast, an upregulation of PLS3 on wild-type level might cause osteoarthritis. This emphasizes that the amount of PLS3 in our cells must be precisely balanced; both too much and too little can be detrimental. Actin-dynamics, regulated by PLS3 among others, are crucial in a lot of cellular processes including endocytosis, cell migration, axonal growth, neurotransmission, translation, and others. Also, PLS3 levels influence the infection with different bacteria, mycosis, and other pathogens.

Keywords: Amyotrophic lateral sclerosis; Ataxia; Colorectal cancer; Cutaneous T-cell lymphomas; Osteoclasts.

Fig. 1

PLS3-associated disorders and main cell types involved. a PLS3 is involved in a variety of diseases, which associate with the PLS3 levels in a cell. Low protein abundance leads to osteoporosis, while increased levels are associated with cancer and osteoarthritis. In some neurodegenerative diseases, where F-actin levels are reduced, PLS3 overexpression acts protective. Green letters imply a protective role of PLS3 while red letters highlight PLS3 as disease driving protein in the depicted disorders. PLS3 plastin 3, SMA spinal muscular atrophy, ALS amyotrophic lateral sclerosis. b PLS3 fulfills distinct functions within different cell types. Osteoclasts, osteoblasts, osteocytes and chondrocytes are the target cells within the bone disease spectrum, which are influenced when PLS3 is dysregulated. In some neurodegenerative disorders, where motor neurons (e.g., SMA) or Purkinje cells (e.g., ataxia) are affected, overexpression of PLS3 showed a protective effect. Involvement of PLS3 in cancer is highly divers and includes different kinds of solid tissues as well as hematopoietic and lymphatic cancers. The figure was created with BioRender.com

Fig. 2

Cellular function of PLS3. The main function of PLS3 is its role in F-actin-binding and -bundling activity and, thus, in F-actin dynamics. Consequently, PLS3 is involved in endocytosis, cell motility, cell adhesion, mechanotransduction, pathogen infection, Ca²⁺ homeostasis, exocytosis, vesicle trafficking, axonal local translation and others. PLS3 protein is depicted as red circle. ER endoplasmic reticulum, ECM extra cellular matrix. The figure was created with BioRender.com

Fig. 3

Schematic representation of the PLS3 gene and corresponding protein domains. Illustrated are the causative mutations for osteoporosis and the resulting amino acid changes that were previously published. All depicted mutations were modified according to HGMD Professional (NM_005032.7 (GRCh38)). References and clinical characterization are shown in Table 2. Note, RNA containing frameshift and nonsense variants (except for the last exon 16), most likely undergo nonsense-mediated mRNA decay and thus no protein is produced. E EF-hand motifs, CBM calmodulin-binding motif, RD regulatory domain, CH calponin-homology domain, ABD actin-binding domain, Core actin-binding core domain, SNP single-nucleotide polymorphism, CNV copy number variation, NA not available; ★ = PLS3 isoform including 18 exons, accession No.: NG_012518. The figure was created with BioRender.com