title: Neddylation requires glycyl-tRNA synthetase to protect activated E2.
abstract: Neddylation is a post-translational modification that controls the cell cycle and proliferation by conjugating the ubiquitin-like protein NEDD8 to specific targets. Here we report that glycyl-tRNA synthetase (GlyRS), an essential enzyme in protein synthesis, also plays a critical role in neddylation. In human cells, knockdown of GlyRS, but not knockdown of a different tRNA synthetase, decreased the global level of neddylation and caused cell-cycle abnormality. This function of GlyRS is achieved through direct interactions with multiple components of the neddylation pathway, including NEDD8, E1, and E2 (Ubc12). Using various structural and functional approaches, we show that GlyRS binds the APPBP1 subunit of E1 and captures and protects activated E2 (NEDD8-conjugated Ubc12) before the activated E2 reaches a downstream target. Therefore, GlyRS functions as a chaperone that critically supports neddylation. This function is probably conserved in all eukaryotic GlyRS enzymes and may contribute to the strong association of GlyRS with cancer progression.
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.|Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Zhongying
authors.initials: Z
authors.lastname: Mo
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.|Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.|Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Ze
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Janelle
authors.initials: J
authors.lastname: Lauer
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.|Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.|Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Litao
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.|Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000401:mortality; D020134:Catalytic Domain; D002453:Cell Cycle; D006032:Glycine-tRNA Ligase / Q000737:chemistry / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D007700:Kinetics; D000075687:NEDD8 Protein; D016016:Proportional Hazards Models; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D059748:Proteolysis; D044764:Ubiquitin-Activating Enzymes / Q000737:chemistry / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry / Q000378:metabolism*; D014452:Ubiquitins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D014452:Ubiquitins; D044763:Ubiquitin-Conjugating Enzymes; D006032:Glycine-tRNA Ligase; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C000596156:UBE2M protein, human