Phosphorylation induced cochaperone unfolding promotes kinase recruitment and client class-specific Hsp90 phosphorylation

Bachman, Ashleigh; Keramisanou, Dimitra; Xu, Wanping; Beebe, Kristin; Moses, Michael A.; Kumar, Milan; Gray, Geoffrey; Noor, Radwan Ebna; Vaart, Arjan van der; Neckers, Len; Gelis, Ioannis

doi:10.1038/s41467-017-02711-w

Cited by 45 publications

(46 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Research during the past few years has provided a clear picture on how co-chaperones and PTMs can be integrated in the functional cycle of Hsp90 and consequently the chaperoning and activity of the client proteins ( Bachman et al, 2018 ; Sahasrabudhe et al, 2017 ; Verba et al, 2016 ). However, it is unclear whether optimal activity of the clients is achieved in a stepwise, controlled manner.…”

Section: Discussionmentioning

confidence: 99%

Post-translational Regulation of FNIP1 Creates a Rheostat for the Molecular Chaperone Hsp90

Sager¹,

Woodford²,

Backe³

et al. 2019

Cell Reports

View full text Add to dashboard Cite

SUMMARY The molecular chaperone Hsp90 stabilizes and activates client proteins. Co-chaperones and post-translational modifications tightly regulate Hsp90 function and consequently lead to activation of clients. However, it is unclear whether this process occurs abruptly or gradually in the cellular context. We show that casein kinase-2 phosphorylation of the co-chaperone folliculin-interacting protein 1 (FNIP1) on priming serine-938 and subsequent relay phosphorylation on serine-939, 941, 946, and 948 promotes its gradual interaction with Hsp90. This leads to incremental inhibition of Hsp90 ATPase activity and gradual activation of both kinase and non-kinase clients. We further demonstrate that serine/threonine protein phosphatase 5 (PP5) dephosphorylates FNIP1, allowing the addition of O -GlcNAc ( O -linked N-acetylglucosamine) to the priming serine-938. This process antagonizes phosphorylation of FNIP1, preventing its interaction with Hsp90, and consequently promotes FNIP1 lysine-1119 ubiquitination and proteasomal degradation. These findings provide a mechanism for gradual activation of the client proteins through intricate crosstalk of post-translational modifications of the co-chaperone FNIP1.

show abstract

Section: Discussionmentioning

confidence: 99%

Post-translational Regulation of FNIP1 Creates a Rheostat for the Molecular Chaperone Hsp90

Sager¹,

Woodford²,

Backe³

et al. 2019

Cell Reports

View full text Add to dashboard Cite

show abstract

“…What defines the Hop requirement of Hsp90 clients remains to be deciphered, but it is clear from our data that the vast majority of Hsp90 clients can be efficiently processed by the prokaryote-like Hsp70-Hsp90 binary complex. We assume that this core molecular chaperone complex still requires the support of other co-chaperones like Hsp40, Cdc37, Aha1 and p23 to select, to process and to release Hsp90 clients (Li et al, 2012;Dunn et al, 2015;Keramisanou et al, 2016;Schopf et al, 2017;Bachman et al, 2018). Compromising the function of these co-chaperones could be particularly detrimental for Hop KO cells running on a somewhat hyperactive Hsp90 machine; indeed, the deletion of 29 SBA1 (encoding the yeast p23 ortholog) in a Dsti1 yeast strain severely reduces cellular fitness (Fang et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

The Hsp70/Hsp90 Co-Chaperone Hop/Stip1 Shifts the Proteostatic Balance from Folding Towards Degradation

Bhattacharya

Weidenauer

Luengo

et al. 2019

Preprint

View full text Add to dashboard Cite

Hop/Stip1/Sti1 is thought to be essential as a co-chaperone to facilitate substrate transfer between the Hsp70 and Hsp90 molecular chaperones. Despite this proposed key function for protein folding and maturation, it is not essential in a number of eukaryotes and bacteria lack an ortholog. We set out to identify and to characterize its eukaryote-specific function. Human cell lines and the budding yeast with deletions of the Hop/Sti1 gene display reduced proteasome activity due to inefficient capping of the core particle with regulatory particles. Unexpectedly, knockout cells are more proficient at preventing protein aggregation and at promoting protein refolding. Without the restraint by Hop, a more efficient folding activity of the prokaryote-like Hsp70/Hsp90 complex, which can also be demonstrated in vitro, compensates for the proteasomal defect and ensures an alternate proteostatic equilibrium. Thus, cells may act on Hop to shift the proteostatic balance between folding and degradation.

show abstract

“…HSP90 is an essential chaperone protein involved in a variety of biological processes, including stabilizing proteins against heat stress, stabilizing a quantity of tumor proteins, and enhancing the loading process of small RNAs into Argonaute proteins (Bachman et al 2018;Karras et al 2017;Taipale et al 2010;Woehrer et al 2015). In mammalian cells, SMYD2 was shown to regulate biological functions of HSP90 by methylating its different domains (Abu-Farha et al 2011).…”

Section: Hsp90 Is a Conserved Smyd Substratementioning

confidence: 99%

Functional analysis of the methyltransferase SMYD in the single-cell model organism Tetrahymena thermophila

Zhao

Duan

et al. 2020

Mar Life Sci Technol

View full text Add to dashboard Cite

Lysine methylation of histones and non-histones plays a pivotal role in diverse cellular processes. The SMYD (SET and MYND domain) family methyltransferases can methylate various histone and non-histone substrates in mammalian systems, implicated in HSP90 methylation, myofilament organization, cancer inhibition, and gene transcription regulation. To resolve controversies concerning SMYD's substrates and functions, we studied SMYD1 (TTHERM_00578660), the only homologue of SMYD in the unicellular eukaryote Tetrahymena thermophila. We epitope-tagged SMYD1, and analyzed its localization and interactome. We also characterized ΔSMYD1 cells, focusing on the replication and transcription phenotype. Our results show that: (1) SMYD1 is present in both cytoplasm and transcriptionally active macronucleus and shuttles between cytoplasm and macronucleus, suggesting its potential association with both histone and non-histone substrates; (2) SMYD1 is involved in DNA replication and regulates transcription of metabolism-related genes; (3) HSP90 is a potential substrate for SMYD1 and it may regulate target selection of HSP90, leading to pleiotropic effects in both the cytoplasm and the nucleus.

show abstract

Phosphorylation induced cochaperone unfolding promotes kinase recruitment and client class-specific Hsp90 phosphorylation

Cited by 45 publications

References 69 publications

Post-translational Regulation of FNIP1 Creates a Rheostat for the Molecular Chaperone Hsp90

Post-translational Regulation of FNIP1 Creates a Rheostat for the Molecular Chaperone Hsp90

The Hsp70/Hsp90 Co-Chaperone Hop/Stip1 Shifts the Proteostatic Balance from Folding Towards Degradation

Functional analysis of the methyltransferase SMYD in the single-cell model organism Tetrahymena thermophila

Contact Info

Product

Resources

About