title: The cochaperone BAG3 coordinates protein synthesis and autophagy under mechanical strain through spatial regulation of mTORC1.
abstract: The cochaperone BAG3 is a central protein homeostasis factor in mechanically strained mammalian cells. It mediates the degradation of unfolded and damaged forms of the actin-crosslinker filamin through chaperone-assisted selective autophagy (CASA). In addition, BAG3 stimulates filamin transcription in order to compensate autophagic disposal and to maintain the actin cytoskeleton under strain. Here we demonstrate that BAG3 coordinates protein synthesis and autophagy through spatial regulation of the mammalian target of rapamycin complex 1 (mTORC1). The cochaperone utilizes its WW domain to contact a proline-rich motif in the tuberous sclerosis protein TSC1 that functions as an mTORC1 inhibitor in association with TSC2. Interaction with BAG3 results in a recruitment of TSC complexes to actin stress fibers, where the complexes act on a subpopulation of mTOR-positive vesicles associated with the cytoskeleton. Local inhibition of mTORC1 is essential to initiate autophagy at sites of filamin unfolding and damage. At the same time, BAG3-mediated sequestration of TSC1/TSC2 relieves mTORC1 inhibition in the remaining cytoplasm, which stimulates protein translation. In human muscle, an exercise-induced association of TSC1 with the cytoskeleton coincides with mTORC1 activation in the cytoplasm. The spatial regulation of mTORC1 exerted by BAG3 apparently provides the basis for a simultaneous induction of autophagy and protein synthesis to maintain the proteome under mechanical strain.
authors.affiliation: Institute for Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kathage
authors.affiliation: German Sport University Cologne, Department of Molecular and Cellular Sport Medicine, Am Sportpark Müngersdorf 6, 50933 Cologne, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Gehlert
authors.affiliation: Institute for Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Ulbricht
authors.affiliation: Institute for Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Lüdecke
authors.affiliation: Department of Medicinal Immunology, Charité - University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Tapia
authors.affiliation: Institute for Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany.
authors.forename: Zacharias
authors.initials: Z
authors.lastname: Orfanos
authors.affiliation: Institute of Physiology I, Life & Brain Center, University Clinic Bonn, Sigmund Freud Str. 25, 53105 Bonn, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Wenzel
authors.affiliation: German Sport University Cologne, Department of Molecular and Cellular Sport Medicine, Am Sportpark Müngersdorf 6, 50933 Cologne, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.affiliation: Department of Medicinal Immunology, Charité - University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Volkmer
authors.affiliation: Institute of Physiology I, Life & Brain Center, University Clinic Bonn, Sigmund Freud Str. 25, 53105 Bonn, Germany.
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Fleischmann
authors.affiliation: Institute for Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany.
authors.forename: Dieter O
authors.initials: DO
authors.lastname: Fürst
authors.affiliation: Institute for Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany. Electronic address: hoehfeld@uni-bonn.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Höhfeld
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D001696:Biomechanical Phenomena; D002460:Cell Line; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D064448:Filamins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding; D014176:Protein Biosynthesis; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D064448:Filamins; D046912:Multiprotein Complexes; D011993:Recombinant Fusion Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Autophagy; Chaperones; Mechanical strain; Protein synthesis; Proteostasis; Signaling