title: Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy.
abstract: 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.
authors: Institute for Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany.
authors: Anna
authors: A
authors: Ulbricht
authors: Felix J
authors: FJ
authors: Eppler
authors: Victor E
authors: VE
authors: Tapia
authors: Peter F M
authors: PF
authors: van der Ven
authors: Nico
authors: N
authors: Hampe
authors: Nils
authors: N
authors: Hersch
authors: Padmanabhan
authors: P
authors: Vakeel
authors: Daniela
authors: D
authors: Stadel
authors: Albert
authors: A
authors: Haas
authors: Paul
authors: P
authors: Saftig
authors: Christian
authors: C
authors: Behrends
authors: Dieter O
authors: DO
authors: Fürst
authors: Rudolf
authors: R
authors: Volkmer
authors: Bernd
authors: B
authors: Hoffmann
authors: Waldemar
authors: W
authors: Kolanus
authors: Jörg
authors: J
authors: Höhfeld
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D040542:Mechanotransduction, Cellular; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D013314:Stress, Mechanical; D014157:Transcription Factors / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D008840:Microfilament Proteins; D018832:Molecular Chaperones; D010750:Phosphoproteins; C503979:SYNPO2 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human