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