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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Laura Mediani - , University of Modena and Reggio Emilia (Author)
  • Francesco Antoniani - , University of Modena and Reggio Emilia (Author)
  • Veronica Galli - , University of Modena and Reggio Emilia (Author)
  • Jonathan Vinet - , University of Modena and Reggio Emilia, IRCCS Fondazione Istituto Neurologico Casimiro Mondino - Pavia (Author)
  • Arianna Dorotea Carrà - , University of Modena and Reggio Emilia (Author)
  • Ilaria Bigi - , University of Modena and Reggio Emilia (Author)
  • Vadreenath Tripathy - , Dresden University of Technology (Author)
  • Tatiana Tiago - , University of Modena and Reggio Emilia (Author)
  • Marco Cimino - , University of Modena and Reggio Emilia (Author)
  • Giuseppina Leo - , University of Modena and Reggio Emilia (Author)
  • Triana Amen - , University of Göttingen (Author)
  • Daniel Kaganovich - , University of Göttingen (Author)
  • Cristina Cereda - , IRCCS Fondazione Istituto Neurologico Casimiro Mondino - Pavia (Author)
  • Orietta Pansarasa - , IRCCS Fondazione Istituto Neurologico Casimiro Mondino - Pavia (Author)
  • Jessica Mandrioli - , University of Modena and Reggio Emilia (Author)
  • Priyanka Tripathi - , RWTH Aachen University (Author)
  • Dirk Troost - , University of Amsterdam (Author)
  • Eleonora Aronica - , University of Amsterdam (Author)
  • Johannes Buchner - , Technical University of Munich (Author)
  • Anand Goswami - , RWTH Aachen University (Author)
  • Jared Sterneckert - , Chair of iPS Cells and Neurodegenerative Diseases (Author)
  • Simon Alberti - , Dresden University of Technology (Author)
  • Serena Carra - , University of Modena and Reggio Emilia (Author)

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.

Details

Original languageEnglish
Article numbere51740
JournalEMBO reports
Volume22
Issue number5
Publication statusPublished - 5 May 2021
Peer-reviewedYes

External IDs

PubMed 33738926
ORCID /0000-0002-7688-3124/work/142250012
ORCID /0000-0003-4017-6505/work/142253798

Keywords

ASJC Scopus subject areas

Keywords

  • DYRK3, FUS-ALS, Hsp90, phase separation, stress granules