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)

• Published in: Nucleic acids research 2017-05, Vol.45 (8), p.4370-4389
• Main Authors: Malecki, Jedrzej, Aileni, Vinay Kumar, Ho, Angela Y Y, Schwarz, Juliane, Moen, Anders, Sørensen, Vigdis, Nilges, Benedikt S, Jakobsson, Magnus E, Leidel, Sebastian A, Falnes, Pål Ø
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Binding Sites; Gene Expression Regulation; Gene regulation, Chromatin and Epigenetics; Guanosine Triphosphate - metabolism; Humans; Lysine - metabolism; Methyltransferases - chemistry; Methyltransferases - genetics; Methyltransferases - metabolism; Organ Specificity; Peptide Elongation Factor 1 - chemistry; Peptide Elongation Factor 1 - genetics; Peptide Elongation Factor 1 - metabolism; Protein Binding; Protein Biosynthesis; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Rats; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Transfer, Amino Acyl - genetics; RNA, Transfer, Amino Acyl - metabolism; Sequence Alignment; Sequence Homology, Amino Acid
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkx002

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.