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Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy.

Authors: Ulbricht, Anna  Eppler, Felix J  Tapia, Victor E  van der Ven, Peter F M  Hampe, Nico  Hersch, Nils  Vakeel, Padmanabhan  Stadel, Daniela  Haas, Albert  Saftig, Paul  Behrends, Christian  Fürst, Dieter O  Volkmer, Rudolf  Hoffmann, Bernd  Kolanus, Waldemar  Höhfeld, Jörg 
Citation: Ulbricht A, etal., Curr Biol. 2013 Mar 4;23(5):430-5. doi: 10.1016/j.cub.2013.01.064. Epub 2013 Feb 21.
Pubmed: (View Article at PubMed) PMID:23434281
DOI: Full-text: DOI:10.1016/j.cub.2013.01.064

Mechanical tension is an ever-present physiological stimulus essential for the development and homeostasis of locomotory, cardiovascular, respiratory, and urogenital systems. Tension sensing contributes to stem cell differentiation, immune cell recruitment, and tumorigenesis. Yet, how mechanical signals are transduced inside cells remains poorly understood. Here, we identify chaperone-assisted selective autophagy (CASA) as a tension-induced autophagy pathway essential for mechanotransduction in muscle and immune cells. The CASA complex, comprised of the molecular chaperones Hsc70 and HspB8 and the cochaperone BAG3, senses the mechanical unfolding of the actin-crosslinking protein filamin. Together with the chaperone-associated ubiquitin ligase CHIP, the complex initiates the ubiquitin-dependent autophagic sorting of damaged filamin to lysosomes for degradation. Autophagosome formation during CASA depends on an interaction of BAG3 with synaptopodin-2 (SYNPO2). This interaction is mediated by the BAG3 WW domain and facilitates cooperation with an autophagosome membrane fusion complex. BAG3 also utilizes its WW domain to engage in YAP/TAZ signaling. Via this pathway, BAG3 stimulates filamin transcription to maintain actin anchoring and crosslinking under mechanical tension. By integrating tension sensing, autophagosome formation, and transcription regulation during mechanotransduction, the CASA machinery ensures tissue homeostasis and regulates fundamental cellular processes such as adhesion, migration, and proliferation.


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CRRD Object Information
CRRD ID: 12793031
Created: 2017-03-18
Species: All species
Last Modified: 2017-03-18
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.