title: Chaperone-assisted selective autophagy is essential for muscle maintenance.
abstract: 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.
authors.affiliation: Institute for Cell Biology and Bonner Forum Biomedizin, University of Bonn, Ulrich-Haberland-Strasse 61a, D-53121 Bonn, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Arndt
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Dick
authors.forename: Riga
authors.initials: R
authors.lastname: Tawo
authors.forename: Michael
authors.initials: M
authors.lastname: Dreiseidler
authors.forename: Daniela
authors.initials: D
authors.lastname: Wenzel
authors.forename: Michael
authors.initials: M
authors.lastname: Hesse
authors.forename: Dieter O
authors.initials: DO
authors.lastname: Fürst
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Robert
authors.initials: R
authors.lastname: Saint
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Fleischmann
authors.forename: Michael
authors.initials: M
authors.lastname: Hoch
authors.forename: Jörg
authors.initials: J
authors.lastname: Höhfeld
mesh_terms: D000818:Animals; D001343:Autophagy; D029721:Drosophila Proteins / Q000502:physiology*; D004331:Drosophila melanogaster / Q000502:physiology*; D009132:Muscles / Q000502:physiology*
chemical_list: D029721:Drosophila Proteins; C513903:stv protein, Drosophila