Force-induced dephosphorylation activates the cochaperone BAG3 to coordinate protein homeostasis and membrane traffic

Ottensmeyer, Judith; Esch, Alessandra; Baeta, Henrique; Sieger, Sandro; Gupta, Yamini; Rathmann, Maximilian F.; Jeschke, Andreas; Jacko, Daniel; Schaaf, Kirill; Schiffer, Thorsten; Rahimi, Bahareh; Lövenich, Lukas; Sisto, Angela; van der Ven, Peter F.M.; Fürst, Dieter O.; Haas, Albert; Bloch, Wilhelm; Gehlert, Sebastian; Hoffmann, Bernd; Timmerman, Vincent; Huesgen, Pitter F.; Höhfeld, Jörg

doi:10.1016/j.cub.2024.07.088

Current Biology

2024

DOI: 10.1016/j.cub.2024.07.088

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Force-induced dephosphorylation activates the cochaperone BAG3 to coordinate protein homeostasis and membrane traffic

Judith Ottensmeyer,

Alessandra Esch,

Henrique Baeta

et al.

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Identification of phosphatases that dephosphorylate the co-chaperone BAG3

Kokot,

Zimmermann,

Chand

et al. 2024

Life Sci. Alliance

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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.

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Identification of phosphatases that dephosphorylate the co-chaperone BAG3

Kokot,

Zimmermann,

Chand

et al. 2024

Life Sci. Alliance

View full text Add to dashboard Cite

show abstract

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Force-induced dephosphorylation activates the cochaperone BAG3 to coordinate protein homeostasis and membrane traffic

Cited by 1 publication

References 93 publications

Identification of phosphatases that dephosphorylate the co-chaperone BAG3

Identification of phosphatases that dephosphorylate the co-chaperone BAG3

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