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

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

EMBO reports (2021-03-20)
Laura Mediani, Francesco Antoniani, Veronica Galli, Jonathan Vinet, Arianna Dorotea Carrà, Ilaria Bigi, Vadreenath Tripathy, Tatiana Tiago, Marco Cimino, Giuseppina Leo, Triana Amen, Daniel Kaganovich, Cristina Cereda, Orietta Pansarasa, Jessica Mandrioli, Priyanka Tripathi, Dirk Troost, Eleonora Aronica, Johannes Buchner, Anand Goswami, Jared Sterneckert, Simon Alberti, Serena Carra
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.

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