Journal
EMBO REPORTS
Volume 22, Issue 5, Pages -Publisher
WILEY
DOI: 10.15252/embr.202051740
Keywords
DYRK3; FUS‐ ALS; Hsp90; phase separation; stress granules
Categories
Funding
- AriSLA Foundation (Granulopathy and MLOpathy)
- Cariplo Foundation [2014-0703]
- MIUR (Departments of excellence 2018-2022) [E91I18001480001]
- MIUR (PRIN, Exo_ALS)
- aegis of JPND
- European Union's Horizon 2020 Research and Innovation Programme [643417]
- European Research Council [725836]
- European Research Council under the European Union's Seventh Framework Program (FP/2007-2013)/ERC-StG2013 [337713]
- Deutsche Forschungsgemeinschaft (DFG)
- CRTD, TUD
- DFG [DFG FZ 111, DFG EXC 168]
- ALS Stichting (grant The Dutch ALS Tissue Bank)
- German Research Foundation (DFG) [WE 1406/16-1]
- European Research Council (ERC) [337713] Funding Source: European Research Council (ERC)
- H2020 Societal Challenges Programme [643417] Funding Source: H2020 Societal Challenges Programme
Ask authors/readers for more resources
Hsp90 is essential for SG dissolution by binding and stabilizing DYRK3, thus linking stress adaptation and cell growth through regulating condensate disassembly and translation restoration.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available