title: Dual specificity kinase DYRK3 couples stress granule condensation/dissolution to mTORC1 signaling.
abstract: Cytosolic compartmentalization through liquid-liquid unmixing, such as the formation of RNA granules, is involved in many cellular processes and might be used to regulate signal transduction. However, specific molecular mechanisms by which liquid-liquid unmixing and signal transduction are coupled remain unknown. Here, we show that during cellular stress the dual specificity kinase DYRK3 regulates the stability of P-granule-like structures and mTORC1 signaling. DYRK3 displays a cyclic partitioning mechanism between stress granules and the cytosol via a low-complexity domain in its N terminus and its kinase activity. When DYRK3 is inactive, it prevents stress granule dissolution and the release of sequestered mTORC1. When DYRK3 is active, it allows stress granule dissolution, releasing mTORC1 for signaling and promoting its activity by directly phosphorylating the mTORC1 inhibitor PRAS40. This mechanism links cytoplasmic compartmentalization via liquid phase transitions with cellular signaling.
authors: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors: Frank
authors: F
authors: Wippich
authors: Bernd
authors: B
authors: Bodenmiller
authors: Maria Gustafsson
authors: MG
authors: Trajkovska
authors: Stefanie
authors: S
authors: Wanka
authors: Ruedi
authors: R
authors: Aebersold
authors: Lucas
authors: L
authors: Pelkmans
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003594:Cytoplasmic Granules / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C484523:AKT1S1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; D012333:RNA, Messenger; C579818:DYRK3 protein, mouse; C408131:DYRK3 protein, human; D011505:Protein-Tyrosine Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases