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57th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN)

German Society for Neuropathology and Neuroanatomy

12. - 15.09.2012, Erlangen

57th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN)

Molecular mechanism of plectin-mediated desmin network anchoring

Meeting Abstract

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  • presenting/speaker Ilona Staszewska - Max F. Perutz Laboratories, University of Vienna, Department of Biochemistry and Cell Biology, Vienna, Austria

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. 57th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN). Erlangen, 12.-15.09.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. Doc12dgnnPP1.17

DOI: 10.3205/12dgnn035, URN: urn:nbn:de:0183-12dgnn0357

Published: September 11, 2012

© 2012 Staszewska.
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Outline

Text

The four major plectin isoforms expressed in muscle are crucial for the integrity of myofibers by specifically targeting and anchoring desmin intermediate filament (IF) networks to Z-disks (plectin 1d), costameres (plectin 1f), mitochondria (plectin 1b), and the outer nuclear/ER membrane system (plectin 1). Yeast two-hybrid screening with a specific skeletal muscle cDNA library and N-terminal fragments of plectin revealed that plectin 1d interacts with two Z-disk proteins: heat shock protein 8 and alpha-actinin-3. Heat shock protein 8 (hsp8) is an important player in a chaperone-assisted selective autophagy (CASA) machinery that constantly operates at Z-disks and removes damaged components in order to keep cellular homeostasis. Alpha-actinin-3 is an actin bundling protein that interacts with many Z-disk proteins. We propose that plectin 1d with its specific N-terminal sequence binds to hsp8/alpha-actinin and links desmin IFs to Z-disks via its C-terminal domain. Upon differentiation the number of Z-disks was decreased in plectin-deficient myotubes compared to plectin-positive cells. Moreover, transfection of full-length plectin 1d into myoblasts rescued Z-disk formation. Our data suggest that plectin by a direct interaction with alpha-actinin stabilizes the Z-disk structure and at the same time forms a platform for the CASA machinery.

We also observed that the shape and size of nuclei in plectin-deficient muscle fibers varied from those in wild-type. As plectin isoform 1 is associated with the outer nuclear/ER membrane system, it probably serves as an anchor for desmin IFs. To confirm that the observed altered nuclear features are indeed plectin 1-dependent, we analyzed nuclei from plectin 1-deficient and plectin-null muscle fibers. We discovered that in the absence of plectin 1, nuclei were larger, more rounded, and had a more regular surface compared to wild-type. These observations clearly showed that plectin isoform 1 maintains the shape of nuclei in muscle. In future studies we will investigate whether plectin 1 influences the positioning and gene expression profile of nuclei during myoblasts differentiation. Furthermore, we will establish the role of plectin 1 in desmin IF-anchoring to the nuclear envelope and characterize outer nuclear membrane proteins interacting with it.