title: Myeloma overexpressed 2 (Myeov2) regulates L11 subnuclear localization through Nedd8 modification.
abstract: Nucleolus is a dynamic structure that controls biogenesis of ribosomal RNA and senses cellular stresses. Nucleolus contains a number of proteins including ribosomal proteins that conduct cellular stresses to downstream signaling such as p53 pathway. Recently, it has been reported that modification by a ubiquitin-like molecule, Nedd8, regulates subnuclear localization of ribosomal protein L11. Most of L11 is normally localized and neddylated in nucleolus. However, cellular stress triggers deneddylation and redistribution of L11, and subsequent activation of p53. Although Nedd8 modification is thought to be important for L11 localization, the mechanism of how neddylation of L11 is regulated remains largely unknown. Here, we show that Myeloma overexpressed 2 (Myeov2) controls L11 localization through down-regulation of Nedd8 modification. Expression of Myeov2 reduced neddylation of proteins including L11. We also found that Myeov2 associates with L11 and withholds L11 in nucleoplasm. Although Myeov2 interacted with a Nedd8 deconjugation enzyme COP9 signalosome, L11 deneddylation was mediated by another deneddylase Nedp1, independently of Myeov2. Finally, p53 transcriptional activity is upregulated by Myeov2 expression. These data demonstrate that Myeov2 hampers L11 neddylation through their interactions and confines L11 to nucleoplasm to modulate nucleolar integrity. Our findings provide a novel link between oncogenic stress and p53 pathway and may shed light on the protective mechanism against cancer.
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Manato
authors.initials: M
authors.lastname: Ebina
authors.forename: Fuminori
authors.initials: F
authors.lastname: Tsuruta
authors.forename: Megumi C
authors.initials: MC
authors.lastname: Katoh
authors.forename: Yu
authors.initials: Y
authors.lastname: Kigoshi
authors.forename: Akie
authors.initials: A
authors.lastname: Someya
authors.forename: Tomoki
authors.initials: T
authors.lastname: Chiba
mesh_terms: D002466:Cell Nucleolus / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D042581:Intranuclear Space / Q000378:metabolism*; D008156:Luciferases; D008954:Models, Biological; D000075687:NEDD8 Protein; D010957:Plasmids / Q000235:genetics; D012269:Ribosomal Proteins / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: C000609535:COPS9 protein, human; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D012269:Ribosomal Proteins; D014452:Ubiquitins; C027624:ribosomal protein L11; D008156:Luciferases