TY - JOUR
T1 - Hsp90-mediated regulation of DYRK3 couples stress granule disassembly and growth via mTORC1 signaling
AU - Mediani, Laura
AU - Antoniani, Francesco
AU - Galli, Veronica
AU - Vinet, Jonathan
AU - Carrà, Arianna Dorotea
AU - Bigi, Ilaria
AU - Tripathy, Vadreenath
AU - Tiago, Tatiana
AU - Cimino, Marco
AU - Leo, Giuseppina
AU - Amen, Triana
AU - Kaganovich, Daniel
AU - Cereda, Cristina
AU - Pansarasa, Orietta
AU - Mandrioli, Jessica
AU - Tripathi, Priyanka
AU - Troost, Dirk
AU - Aronica, Eleonora
AU - Buchner, Johannes
AU - Goswami, Anand
AU - Sterneckert, Jared
AU - Alberti, Simon
AU - Carra, Serena
N1 - Funding Information: S.C. acknowledges funding from AriSLA Foundation (Granulopathy and MLOpathy); Cariplo Foundation (Rif. 2014-0703); MIUR (Departments of excellence 2018-2022, E91I18001480001 and PRIN, Exo_ALS). S.C. and S.A. are grateful to EU Joint Programme?Neurodegenerative Disease Research (JPND) project. The project is supported through funding organizations under the aegis of JPND (http://www.neurodegenerationresearch.eu/). This project has received funding from the European Union?s Horizon 2020 Research and Innovation Programme under grant agreement No 643417. S.A. acknowledges funding from European Research Council (grant number 725836). S.C. and D.K. are grateful to MAECI and The Israeli Ministry of Science and Technology (Dissolve_ALS). D.K. was supported by the European Research Council under the European Union's Seventh Framework Program (FP/2007-2013)/ERC-StG2013 337713 DarkSide starting grant. J.S. acknowledges funding from the Deutsche Forschungsgemeinschaft (DFG) and the CRTD, which is part of the TUD. J.S. was financed by the DFG Research Center (DFG FZ 111) and Cluster of Excellence (DFG EXC 168), including a seed grant. We acknowledge and thank the CMCB Light Microscopy facility for their assistance. We thank CIGS (University of Modena microscopy facility) for technical support and Dr. TM Franzmann (University of Dresden) for providing the FRAP analysis script. We thank Dr. Picard and Dr. Pelkmans for kindly providing us vectors coding for mCherry-Hsp90 and GFP-DYRK3 WT and dN. We acknowledge the team that contributed to the establishment of the Dutch ALS Tissue Bank, as well as the team that contributed to the collection of ALS tissue samples (Prof. Dr. D. Troost, Prof. Dr. M. de Visser, Dr. A.J. van der Kooi, Dr. J. Raaphorst) and J. Anink (AMC, Amsterdam) for providing technical support. E.A. is supported by the ALS Stichting (grant ?The Dutch ALS Tissue Bank?) and the neuropathological work-up at the Institute of Neuropathology is supported by the German Research Foundation (DFG; WE 1406/16-1). Publisher Copyright: © 2021 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2021/5/5
Y1 - 2021/5/5
N2 - Stress granules (SGs) are dynamic condensates associated with protein misfolding diseases. They sequester stalled mRNAs and signaling factors, such as the mTORC1 subunit raptor, suggesting that SGs coordinate cell growth during and after stress. However, the molecular mechanisms linking SG dynamics and signaling remain undefined. We report that the chaperone Hsp90 is required for SG dissolution. Hsp90 binds and stabilizes the dual-specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3) in the cytosol. Upon Hsp90 inhibition, DYRK3 dissociates from Hsp90 and becomes inactive. Inactive DYRK3 is subjected to two different fates: it either partitions into SGs, where it is protected from irreversible aggregation, or it is degraded. In the presence of Hsp90, DYRK3 is active and promotes SG disassembly, restoring mTORC1 signaling and translation. Thus, Hsp90 links stress adaptation and cell growth by regulating the activity of a key kinase involved in condensate disassembly and translation restoration.
AB - Stress granules (SGs) are dynamic condensates associated with protein misfolding diseases. They sequester stalled mRNAs and signaling factors, such as the mTORC1 subunit raptor, suggesting that SGs coordinate cell growth during and after stress. However, the molecular mechanisms linking SG dynamics and signaling remain undefined. We report that the chaperone Hsp90 is required for SG dissolution. Hsp90 binds and stabilizes the dual-specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3) in the cytosol. Upon Hsp90 inhibition, DYRK3 dissociates from Hsp90 and becomes inactive. Inactive DYRK3 is subjected to two different fates: it either partitions into SGs, where it is protected from irreversible aggregation, or it is degraded. In the presence of Hsp90, DYRK3 is active and promotes SG disassembly, restoring mTORC1 signaling and translation. Thus, Hsp90 links stress adaptation and cell growth by regulating the activity of a key kinase involved in condensate disassembly and translation restoration.
KW - DYRK3
KW - FUS-ALS
KW - Hsp90
KW - phase separation
KW - stress granules
UR - http://www.scopus.com/inward/record.url?scp=85102648206&partnerID=8YFLogxK
U2 - https://doi.org/10.15252/embr.202051740
DO - https://doi.org/10.15252/embr.202051740
M3 - Article
C2 - 33738926
SN - 1469-221X
VL - 22
JO - EMBO reports
JF - EMBO reports
IS - 5
M1 - e51740
ER -