title: The novel lysine specific methyltransferase METTL21B affects mRNA translation through inducible and dynamic methylation of Lys-165 in human eukaryotic elongation factor 1 alpha (eEF1A).
abstract: Lysine methylation is abundant on histone proteins, representing a dynamic regulator of chromatin state and gene activity, but is also frequent on many non-histone proteins, including eukaryotic elongation factor 1 alpha (eEF1A). However, the functional significance of eEF1A methylation remains obscure and it has remained unclear whether eEF1A methylation is dynamic and subject to active regulation. We here demonstrate, using a wide range of in vitro and in vivo approaches, that the previously uncharacterized human methyltransferase METTL21B specifically targets Lys-165 in eEF1A in an aminoacyl-tRNA- and GTP-dependent manner. Interestingly, METTL21B-mediated eEF1A methylation showed strong variation across different tissues and cell lines, and was induced by altering growth conditions or by treatment with certain ER-stress-inducing drugs, concomitant with an increase in METTL21B gene expression. Moreover, genetic ablation of METTL21B function in mammalian cells caused substantial alterations in mRNA translation, as measured by ribosomal profiling. A non-canonical function for eEF1A in organization of the cellular cytoskeleton has been reported, and interestingly, METTL21B accumulated in centrosomes, in addition to the expected cytosolic localization. In summary, the present study identifies METTL21B as the enzyme responsible for methylation of eEF1A on Lys-165 and shows that this modification is dynamic, inducible and likely of regulatory importance.
authors.affiliation: Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway.
authors.forename: Jedrzej
authors.initials: J
authors.lastname: Malecki
authors.affiliation: Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway.
authors.forename: Vinay Kumar
authors.initials: VK
authors.lastname: Aileni
authors.affiliation: Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway.
authors.forename: Angela Y Y
authors.initials: AYY
authors.lastname: Ho
authors.affiliation: Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, 48149 Muenster, Germany.|Cells-in-Motion Cluster of Excellence, University of Muenster, 48149 Muenster, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Schwarz
authors.affiliation: Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Moen
authors.affiliation: Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, 0379 Oslo, Norway.
authors.forename: Vigdis
authors.initials: V
authors.lastname: Sørensen
authors.affiliation: Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, 48149 Muenster, Germany.|Cells-in-Motion Cluster of Excellence, University of Muenster, 48149 Muenster, Germany.
authors.forename: Benedikt S
authors.initials: BS
authors.lastname: Nilges
authors.affiliation: Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway.
authors.forename: Magnus E
authors.initials: ME
authors.lastname: Jakobsson
authors.affiliation: Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, 48149 Muenster, Germany.|Cells-in-Motion Cluster of Excellence, University of Muenster, 48149 Muenster, Germany.
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Leidel
authors.affiliation: Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway.
authors.forename: Pål Ø
authors.initials: PØ
authors.lastname: Falnes
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D005786:Gene Expression Regulation; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008780:Methyltransferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D020648:Peptide Elongation Factor 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D012346:RNA, Transfer, Amino Acyl / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: C094814:EEF1A1 protein, human; D020648:Peptide Elongation Factor 1; D012333:RNA, Messenger; D012346:RNA, Transfer, Amino Acyl; D006160:Guanosine Triphosphate; C000622448:EEF1AKMT3 protein, human; D008780:Methyltransferases; D008239:Lysine