Chaperone-Assisted Selective Autophagy Is Essential for Muscle Maintenance

How are biological structures maintained in a cellular environment that constantly threatens protein integrity? Here we elucidate proteostasis mechanisms affecting the Z disk, a protein assembly essential for actin anchoring in striated muscles, which is subjected to mechanical, thermal, and oxidati...

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Bibliographic Details
Published in:Current biology 2010-01, Vol.20 (2), p.143-148
Main Authors: Arndt, Verena, Dick, Nikolaus, Tawo, Riga, Dreiseidler, Michael, Wenzel, Daniela, Hesse, Michael, Fürst, Dieter O., Saftig, Paul, Saint, Robert, Fleischmann, Bernd K., Hoch, Michael, Höhfeld, Jörg
Format: Article
Language:English
Subjects:
Animals
Autophagy
CELLBIO
Drosophila melanogaster - physiology
Drosophila Proteins - physiology
HUMDISEASE
Muscles - physiology
PROTEINS
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Summary:How are biological structures maintained in a cellular environment that constantly threatens protein integrity? Here we elucidate proteostasis mechanisms affecting the Z disk, a protein assembly essential for actin anchoring in striated muscles, which is subjected to mechanical, thermal, and oxidative stress during contraction [1]. Based on the characterization of the Drosophila melanogaster cochaperone Starvin (Stv), we define a conserved chaperone machinery required for Z disk maintenance. Instead of keeping Z disk proteins in a folded conformation, this machinery facilitates the degradation of damaged components, such as filamin, through chaperone-assisted selective autophagy (CASA). Stv and its mammalian ortholog BAG-3 coordinate the activity of Hsc70 and the small heat shock protein HspB8 during disposal that is initiated by the chaperone-associated ubiquitin ligase CHIP and the autophagic ubiquitin adaptor p62. CASA is thus distinct from chaperone-mediated autophagy, previously shown to facilitate the ubiquitin-independent, direct translocation of a client across the lysosomal membrane [2]. Impaired CASA results in Z disk disintegration and progressive muscle weakness in flies, mice, and men. Our findings reveal the importance of chaperone-assisted degradation for the preservation of cellular structures and identify muscle as a tissue that highly relies on an intact proteostasis network, thereby shedding light on diverse myopathies and aging. ► The cochaperones BAG-3 and Starvin (Stv) are essential for Z disk maintenance ► Damaged filamin needs to be continuously degraded by autophagy to preserve muscles ► Impaired CASA is the cause of severe childhood myopathy ► The ubiquitin ligase CHIP initiates proteasomal and autophagic degradation
ISSN:0960-9822
1879-0445
DOI:10.1016/j.cub.2009.11.022