Identification of phosphatases that dephosphorylate the co-chaperone BAG3.

Autor:	Kokot T; Institute of Biology III, Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg im Breisgau, Germany., Zimmermann JP; Biochemistry II, Theodor-Boveri-Institute, University of Würzburg, Würzburg, Germany., Chand Y; Institute of Biology III, Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg im Breisgau, Germany., Krier F; Institute of Biology III, Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg im Breisgau, Germany., Reimann L; Biochemistry and Functional Proteomics, Institute of Biology II, Faculty of Biology, University of Freiburg, Freiburg, Germany., Scheinost L; Institute of Biology III, Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg im Breisgau, Germany., Höfflin N; Institute of Biology III, Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg im Breisgau, Germany., Esch A; Institute for Cell Biology, University of Bonn, Bonn, Germany., Höhfeld J; Institute for Cell Biology, University of Bonn, Bonn, Germany., Warscheid B; Biochemistry II, Theodor-Boveri-Institute, University of Würzburg, Würzburg, Germany.; Biochemistry and Functional Proteomics, Institute of Biology II, Faculty of Biology, University of Freiburg, Freiburg, Germany., Köhn M; Institute of Biology III, Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany mkoehn@uni-bonn.de.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg im Breisgau, Germany.; Institute for Cell Biology, University of Bonn, Bonn, Germany.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2024 Nov 19; Vol. 8 (2). Date of Electronic Publication: 2024 Nov 19 (Print Publication: 2025).
DOI:	10.26508/lsa.202402734
Abstrakt:	The co-chaperone BAG3 plays critical roles in maintaining cellular proteostasis. It associates with 14-3-3 proteins during the trafficking of aggregation-prone proteins and facilitates their degradation through chaperone-assisted selective autophagy in cooperation with small heat shock proteins. Although reversible phosphorylation regulates BAG3 function, the involved phosphatases remain unknown. Here, we used affinity purification mass spectrometry to identify phosphatases that target BAG3. Of the hits, we evaluated the involvement of protein phosphatase-1 (PP1) using chemical inhibitors and activators in in vitro and cellular approaches. Our results demonstrate that PP1 can dephosphorylate BAG3-pS136 in cells and counteract 14-3-3γ association with BAG3 at this motif. Furthermore, protein phosphatase-5 (PP5) co-enriched with proteostasis-related proteins, and it has the capacity to dephosphorylate a BAG3 phosphorylation-site cluster regulating the interaction of BAG3 with small heat shock proteins and BAG3-mediated protein degradation. Our findings provide new insights into the regulation of BAG3 by phosphatases. This paves the way for future research focused on the precise control of BAG3 function through its regulatory proteins, potentially holding therapeutic promise for diseases characterized by disrupted proteostasis. (© 2024 Kokot et al.)
Databáze:	MEDLINE
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