1. The cochaperone BAG3 coordinates protein synthesis and autophagy under mechanical strain through spatial regulation of mTORC1.
- Author
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Kathage B, Gehlert S, Ulbricht A, Lüdecke L, Tapia VE, Orfanos Z, Wenzel D, Bloch W, Volkmer R, Fleischmann BK, Fürst DO, and Höhfeld J
- Subjects
- Actin Cytoskeleton metabolism, Actin Cytoskeleton ultrastructure, Adaptor Proteins, Signal Transducing metabolism, Amino Acid Sequence, Animals, Apoptosis Regulatory Proteins metabolism, Biomechanical Phenomena, Cell Line, Cloning, Molecular, Escherichia coli genetics, Escherichia coli metabolism, Filamins genetics, Filamins metabolism, Gene Expression, Gene Expression Regulation, Humans, Mechanistic Target of Rapamycin Complex 1, Mice, Multiprotein Complexes metabolism, Muscle, Skeletal cytology, Myocytes, Smooth Muscle ultrastructure, Protein Binding, Protein Biosynthesis, Rats, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Signal Transduction, TOR Serine-Threonine Kinases metabolism, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Adaptor Proteins, Signal Transducing genetics, Apoptosis Regulatory Proteins genetics, Autophagy genetics, Multiprotein Complexes genetics, Muscle, Skeletal metabolism, Myocytes, Smooth Muscle metabolism, Stress, Mechanical, TOR Serine-Threonine Kinases genetics
- 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., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2017
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