title: p38MAPK/MK2-mediated phosphorylation of RBM7 regulates the human nuclear exosome targeting complex.
abstract: The nuclear exosome targeting complex (NEXT) directs a major 3'-5' exonuclease, the RNA exosome, for degradation of nuclear noncoding (nc) RNAs. We identified the RNA-binding component of the NEXT complex, RBM7, as a substrate of p38(MAPK)/MK2-mediated phosphorylation at residue S136. As a result of this phosphorylation, RBM7 displays a strongly decreased RNA-binding capacity, while inhibition of p38(MAPK) or mutation of S136A in RBM7 increases its RNA association. Interestingly, promoter-upstream transcripts (PROMPTs), such as proRBM39, proEXT1, proDNAJB4, accumulated upon stress stimulation in a p38(MAPK)/MK2-dependent manner, a process inhibited by overexpression of RBM7(S136A). While there are no stress-dependent changes in RNA-polymerase II (RNAPII) occupation of PROMPT regions representing unchanged transcription, stability of PROMPTs is increased. Hence, we propose that phosphorylation of RBM7 by the p38(MAPK)/MK2 axis increases nuclear ncRNA stability by blocking their RBM7-binding and subsequent RNA exosome targeting to allow stress-dependent modulations of the noncoding transcriptome.
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, 30625 Hannover, Germany Tiedje.Christopher@mh-hannover.de Gaestel.Matthias@mh-hannover.de.
authors.forename: Christopher
authors.initials: C
authors.lastname: Tiedje
authors.affiliation: Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Michal
authors.initials: M
authors.lastname: Lubas
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Tehrani
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Manoj B
authors.initials: MB
authors.lastname: Menon
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Ronkina
authors.affiliation: MRC Phosphorylation und Ubiquitylation Unit (MRC-PPU), Dundee, Scotland DD1 5EH, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Rousseau
authors.affiliation: MRC Phosphorylation und Ubiquitylation Unit (MRC-PPU), Dundee, Scotland DD1 5EH, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Cohen
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Alexey
authors.initials: A
authors.lastname: Kotlyarov
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, 30625 Hannover, Germany Tiedje.Christopher@mh-hannover.de Gaestel.Matthias@mh-hannover.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D055354:Exosomes; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020871:RNA Stability; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D013312:Stress, Physiological; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D022661:RNA, Untranslated; D016601:RNA-Binding Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C000596172:RBM7 protein, human; C506699:ZCCHC8 protein, human
keywords: RBM7; RNA binding; RNA stability; ncRNAs; p38MAPK/MK2 signaling; phosphorylation