Hsp90-mediated regulation of DYRK3 couples stress granule disassembly and growth via mTORC1 signaling.

Laura Mediani,Jessica Mandrioli,Priyanka Tripathi,Triana Amen,Jared Sterneckert,Serena Carra,Orietta Pansarasa,Giuseppina Leo,Eleonora Aronica,Simon Alberti,Jonathan Vinet,Anand Goswami,Ilaria Bigi,Vadreenath Tripathy,Dirk Troost,Veronica Galli,Francesco Antoniani,Tatiana Tiago,Marco Cimino,Cristina Cereda,Daniel Kaganovich,Arianna Dorotea Carrà,Johannes Büchner

doi:10.15252/embr.202051740

Abstract

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.

Highlights

Stress granules (SGs) are dynamic condensates associated with protein misfolding diseases
Using time-lapse microscopy and HeLa-Kyoto cells expressing the SG marker G3BP2-GFP, we confirmed that most sodium arsenite induced SGs disassemble when the stress is removed; SGs dissolved regardless of whether lysosomal proteases were inactivated with ammonium chloride (Fig EV1A and Movie EV1), suggesting that autophagy does not play a major role
Delayed SG disassembly upon Hsp90 inhibition could be reproduced in a different cell line (Fig EV1C and D, and Movies EV3 and EV4, PABPC1-Dendra2 HEK293T cells) and was observed when Hsp90 levels were reduced by siRNA-mediated knockdown (Fig 1C and D and Movie EV5)

Summary

Introduction

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. The molecular mechanisms linking SG dynamics and signaling remain undefined. Hsp binds and stabilizes the dual-specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3) in the cytosol. 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 Hsp, DYRK3 is active and promotes SG disassembly, restoring mTORC1 signaling and translation. Hsp links stress adaptation and cell growth by regulating the activity of a key kinase involved in condensate disassembly and translation restoration

Methods

Results

Conclusion