Developmental Biology & Disease Mechanisms | Molecular Cell Biology
Cytoskeletal linker proteins in development, stress response, and disease
The cytoskeleton provides the structural basis for physical robustness, shape, movement, and intracellular dynamics of eukaryotic cells. In muscle cells, it forms the contractile apparatus, confers structural support and positions organelles; in neurons, it maintains the asymmetric cell shape and polarity; and in epithelial cells, it plays a pivotal role in maintaining cell and tissue integrity. We are interested in cytoskeletal linker proteins (cytolinkers), a...more
The cytoskeleton provides the structural basis for physical robustness, shape, movement, and intracellular dynamics of eukaryotic cells. In muscle cells, it forms the contractile apparatus, confers structural support and positions organelles; in neurons, it maintains the asymmetric cell shape and polarity; and in epithelial cells, it plays a pivotal role in maintaining cell and tissue integrity. We are interested in cytoskeletal linker proteins (cytolinkers), a family of multi-modular, highly versatile proteins of exceptional size, that by networking and anchoring cytoskeletal filaments regulate cytoskeleton dynamics and architecture. We are studying the role of cytolinkers in normal development, cellular stress response, and disease, combining mouse genetics with cell and structural biology.
Several years ago we discovered plectin, a ubiquitous cytolinker that became the prototype of what meanwhile is a whole family of similar proteins. Plectin has key functions in shaping cell architecture, mechanical stabilization and polarization of cells, positioning of organelles, signal transduction and nerve conduction. Thus, loss or dysfunction of plectin leads to diseases affecting a variety of cell types and tissues. Plectin’s versatility is based on an unusual diversity of isoforms differing in small N-terminal sequences that determine the protein’s localization. We have generated a panel of transgenic mouse lines, including full knockout (KO), single isoform and conditional/tissue-restricted KO, and knock-in lines. Serving us in analyzing isoform-specific functions and providing animal models for plectin-related human diseases, we use these systems focusing on:
We found myofiber integrity, including mitochondrial function, in skeletal muscle to be dependent on the proper targeting of desmin intermediate filament (IF) networks to strategic cellular sites via distinct plectin isoforms. Plectin-unanchored desmin networks collapse and form protein aggregates leading to dysfunctional myofibers. In addition, unbalanced plectin levels cause diabetes. Other topics are plectin-related heart dysfunctions and failures in myofiber regeneration (Fig. on left).
Plectin in epithelia (skin)
Severe skin blistering (EBS) is the hallmark of most plectinopathies. The analysis of a knock-in mouse line mimicking the dominant plectin mutation of EBS-Ogna patients provided new insights into hemidesmosome(HD)-stabilizing mechanisms and revealed plectin-isoform-specific proteolysis as a novel mechanism regulating HD-homeostasis.
Role of plectin in neural cells
Having identified the major neuronal plectin-isoform as a microtubule regulator, we are assessing its role in synaptic transmission, nerve conduction, and glucose uptake.
Plectin-dependent signaling and stress response in endothelial and fibroblast cells. We found plectin scaffolds to antagonize oxidative stress-mediated alterations of cell cytoarchitecture. Present studies are focused on plectin’s role in stress response of endothelial and fibroblast cells (Fig. on left).
Wiche, G., Osmanagic-Myers, S., and Castañón, M.J. (2015). Networking and anchoring through plectin: a key to IF functionality and mechanotransduction CURR OPIN CELL BIOL:21-29 . PMID: 25460778
Lilli Winter, Ilona Staszewska, Eva Mihailovska, Irmgard Fischer1, Wolfgang H. Goldmann, Rolf Schröder and Gerhard Wiche (2014). Chemical chaperone ameliorates pathological protein aggregation in plectin-deficient muscle J CLIN INVEST;124(3):11441157. PMID: 24487589
Mihailovska, Eva; Raith, Marianne; Valencia, Rocio G; Fischer, Irmgard; Banchaabouchi, Mumna Al; Herbst, Ruth; Wiche, Gerhard (2014). Neuromuscular synapse integrity requires linkage of acetylcholine receptors to postsynaptic intermediate filament networks via rapsyn-plectin 1f complexes. MOL BIOL CELL;25(25):4130-49. PMID: 25318670