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The cytoskeleton provides the structural basis for physical robustness, shape, movement, and intracellular dynamics of eukaryotic cells. It forms the contractile apparatus in muscle, confers structural support, positions organelles, maintains the asymmetric shape and polarity of neurons, and plays pivotal roles in maintaining cell integrity, eg in epithelial cells, and in processes involving cell migration, such as wound healing, immune response, and tumor metastasis. We are primarily interested in plectin, a large multi-modular, multi-functional cytolinker protein that we identified as a global regulator of cytoskeleton dynamics, cell shape, compartmentalization, and mechanotransduction. Dysfunctional plectin results in multisystemic disorders (skin, muscle, vasculature, nerve, etc), while translocation of plectin to the cell surface is a hallmark of multiple cancers. Our goal is to understand mechanistically how plectin works under physiological and pathological conditions.
To study plectin functions we are combining mouse genetics with cell and structural biology. We found an unusual diversity of plectin isoforms that are differentially targeted to strategic cellular locations, including focal contacts, adhesion junctions, hemidesmosomes, the nuclear and ER membrane, mitochondria, the neuromuscular synapse, Z-disks, costameres, and others, thereby recruiting and anchoring intermediate filaments (IFs), the mechanically most resistant and least dynamic cytoskeleton component, to these sites. Cell type-specific expression of distinct isoforms thus affects cytoarchitecture and cell performance. To dissect isoform-specific functions and provide animal models for plectin-related diseases (plectinopathies) we have generated and are analyzing a panel of transgenic mouse lines, including full knockout (KO), single isoform and conditional/tissue-restricted KO, double KO, and knock-in lines.
Gerhard Wiche (Professor Emeritus) studied Biochemistry/Chemistry at the University of Vienna (PhD 1971). After 5 years as postdoctoral fellow and research associate in the USA (Roche IMB, NJ; UC Berkeley, CA), he started his own group at the Medical School and in 1990 took a position as Full Professor for Molecular Cell Biology at the University of Vienna (sabbaticals: Chicago, Paris, Madrid).
Plectin deficiency in skeletal muscle leads to desmin IF network aggregation and loss of myofiber integrity. Using immortalized, differentiation-competent myoblast cell cultures established from plectin-KO mouse muscle for drug screening, we found a chemical chaperone (4-PBA) that alleviates protein aggregation and increases muscle strength in mice, setting the stage for clinical studies.
Severe skin blistering is the hallmark of most plectinopathies. The analysis of knock-in mice mimicking a dominant human plectin mutation provided new insights into the function of isoform P1a and hemidesmosome-stabilizing mechanisms based on plectin oligomerization (see micrograph). In situ cleavage of P1a by proteases (calpain-1) was revealed as the likely pathomechanism of the disease EBS-Ogna.
P1c is the major isoform of plectin expressed in neurons and glial cells. Mice specifically lacking P1c show learning and long-term memory deficits. We found that P1c (contrary to other variants) binds to microtubules favoring their dynamics by counteracting stabilization. Presently, we are investigating mechanistic links between plectin-mediated cytoskeleton rearrangements and memory formation.
Plectin together with its IF partner vimentin is strongly upregulated in several types of cancer, and is being developed as a tumor cell surface biomarker. In highly invasive cancer cells, formation of cellular protrusions (invadopodia) penetrating surrounding matrices is strictly plectin-dependent. We are interested in the mechanisms involving plectin-mediated exosome secretion and metastases.
Neuromuscular synapse integrity requires linkage of acetylcholine receptors to postsynaptic intermediate filament networks via rapsyn-plectin 1f complexes.
Mihailovska, Eva; Raith, Marianne; Valencia, Rocio G; Fischer, Irmgard; Banchaabouchi, Mumna Al; Herbst, Ruth; Wiche, Gerhard
Chemical chaperone ameliorates pathological protein aggregation in plectin-deficient muscle
Lilli Winter, Ilona Staszewska, Eva Mihailovska, Irmgard Fischer1, Wolfgang H. Goldmann, Rolf Schröder and Gerhard Wiche
Networking and anchoring through plectin: a key to IF functionality and mechanotransduction
Wiche, G., Osmanagic-Myers, S., and Castañón, M.J.
The Group Wiche participates in the special Doctoral Program "Molecular Mechanisms of Cell Signaling" reviewed and funded by the Austrian Research Fund FWF.