Z-Disk-Associated Plectin (Isoform 1d): Spatial Arrangement, Interaction Partners, and Role in Filamin C Homeostasis

Lilli Winter; Ilona Staszewska-Daca; Stefan Zittrich; Fatiha Elhamine; Michaela M. Zrelski; Katy Schmidt; Irmgard Fischer; Christian Jüngst; Astrid Schauss; Wolfgang H. Goldmann; Robert Stehle; Gerhard Wiche

doi:10.3390/cells12091259

Titel

Z-Disk-Associated Plectin (Isoform 1d): Spatial Arrangement, Interaction Partners, and Role in Filamin C Homeostasis

Autor*in

Lilli Winter

Department für Biochemie und Zellbiologie, Max Perutz Labs, Universität Wien

Ilona Staszewska-Daca

Department für Biochemie und Zellbiologie, Max Perutz Labs, Universität Wien

Stefan Zittrich

Institute of Vegetative Physiology, Medical Faculty, University of Cologne

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Abstract

Plectin, a highly versatile cytolinker protein, is crucial for myofiber integrity and function. Accordingly, mutations in the human gene (PLEC) cause several rare diseases, denoted as plectinopathies, with most of them associated with progressive muscle weakness. Of several plectin isoforms expressed in skeletal muscle and the heart, P1d is the only isoform expressed exclusively in these tissues. Using high-resolution stimulated emission depletion (STED) microscopy, here we show that plectin is located within the gaps between individual α-actinin-positive Z-disks, recruiting and bridging them to desmin intermediate filaments (IFs). Loss of plectin in myofibril bundles led to a complete loss of desmin IFs. Loss of Z-disk-associated plectin isoform P1d led to disorganization of muscle fibers and slower relaxation of myofibrils upon mechanical strain, in line with an observed inhomogeneity of muscle ultrastructure. In addition to binding to α-actinin and thereby providing structural support, P1d forms a scaffolding platform for the chaperone-assisted selective autophagy machinery (CASA) by directly interacting with HSC70 and synpo2. In isoform-specific knockout (P1d-KO) mouse muscle and mechanically stretched plectin-deficient myoblasts, we found high levels of undigested filamin C, a bona fide substrate of CASA. Similarly, subjecting P1d-KO mice to forced swim tests led to accumulation of filamin C aggregates in myofibers, highlighting a specific role of P1d in tension-induced proteolysis activated upon high loads of physical exercise and muscle contraction.

Stichwort

plectinskeletal musclemyofibrilcytolinkerdesmin intermediate filamentschaperone-assisted selective autophagy

Objekt-Typ

journal article

Sprache

Englisch [eng]

Persistent identifier

phaidra.univie.ac.at/o:2068820

DOI

10.3390/cells12091259

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