title: p38- and MK2-dependent signalling promotes stress-induced centriolar satellite remodelling via 14-3-3-dependent sequestration of CEP131/AZI1.
abstract: Centriolar satellites (CS) are small granular structures that cluster in the vicinity of centrosomes. CS are highly susceptible to stress stimuli, triggering abrupt displacement of key CS factors. Here we discover a linear p38-MK2-14-3-3 signalling pathway that specifically targets CEP131 to trigger CS remodelling after cell stress. We identify CEP131 as a substrate of the p38 effector kinase MK2 and pinpoint S47 and S78 as critical MK2 phosphorylation sites in CEP131. Ultraviolet-induced phosphorylation of these residues generates direct binding sites for 14-3-3 proteins, which sequester CEP131 in the cytoplasm to block formation of new CS, thereby leading to rapid depletion of these structures. Mutating S47 and S78 in CEP131 is sufficient to abolish stress-induced CS reorganization, demonstrating that CEP131 is the key regulatory target of MK2 and 14-3-3 in these structures. Our findings reveal the molecular mechanism underlying dynamic CS remodelling to modulate centrosome functions on cell stress.
authors.affiliation: Ubiquitin Signaling Group, Protein Signaling Program, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen DK-2200, Denmark.
authors.forename: Maxim A X
authors.initials: MAX
authors.lastname: Tollenaere
authors.affiliation: Ubiquitin Signaling Group, Protein Signaling Program, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen DK-2200, Denmark.
authors.forename: Bine H
authors.initials: BH
authors.lastname: Villumsen
authors.affiliation: Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, Denmark.
authors.forename: Melanie
authors.initials: M
authors.lastname: Blasius
authors.affiliation: Ubiquitin Signaling Group, Protein Signaling Program, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen DK-2200, Denmark.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Nielsen
authors.affiliation: Department of Medicine, Hematology/Oncology, Goethe University Medical School, Theodor-Stern-Kai 7, Frankfurt DE-60590, Germany.
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Wagner
authors.affiliation: Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, Denmark.|Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm SE-17176, Sweden.
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.affiliation: Institute of Molecular Biology, Ackermannweg 4, Mainz DE-55128, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Beli
authors.affiliation: Ubiquitin Signaling Group, Protein Signaling Program, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen DK-2200, Denmark.
authors.forename: Niels
authors.identifier: http://orcid.org/0000-0002-6623-709X
authors.initials: N
authors.lastname: Mailand
authors.affiliation: Ubiquitin Signaling Group, Protein Signaling Program, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen DK-2200, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Bekker-Jensen
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002502:Centrioles / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008868:Microtubule Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D048948:14-3-3 Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008868:Microtubule Proteins; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C578334:CEP131 protein, human; C482983:YWHAE protein, human; C572235:YWHAZ protein, human