title: Stoichiometry of the eIF2B complex is maintained by mutual stabilization of subunits.
abstract: The eukaryotic translation initiation factor eIF2B is a multi-subunit complex with a crucial role in the regulation of global protein synthesis in the cell. The complex comprises five subunits, termed α through ε in order of increasing size, arranged as a heterodecamer with two copies of each subunit. Regulation of the co-stoichiometric expression of the eIF2B subunits is crucial for the proper function and regulation of the eIF2B complex in cells. We have investigated the control of stoichiometric eIF2B complexes through mutual stabilization of eIF2B subunits. Our data show that the stable expression of the catalytic eIF2Bε subunit in human cells requires co-expression of eIF2Bγ. Similarly, stable expression of eIF2Bδ requires both eIF2Bβ and eIF2Bγ+ε. The expression of these subunits decreases despite there being no change in either the levels or the translation of their mRNAs. Instead, these subunits are targeted for degradation by the ubiquitin-proteasome system. The data allow us to propose a model for the formation of stoichiometric eIF2B complexes which can ensure their stoichiometric incorporation into the holocomplex.
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, U.K.
authors.forename: Noel C
authors.initials: NC
authors.lastname: Wortham
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, U.K.
authors.forename: Joanna D
authors.initials: JD
authors.lastname: Stewart
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, U.K.
authors.forename: Sean
authors.initials: S
authors.lastname: Harris
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, U.K.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Coldwell
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, U.K. christopher.proud@sahmri.com.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Proud
mesh_terms: D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D049409:Luciferases, Firefly / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011132:Polyribosomes / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D054875:Ubiquitination
chemical_list: D020717:Eukaryotic Initiation Factor-2B; D021122:Protein Subunits; D034741:RNA, Small Interfering; D049409:Luciferases, Firefly
keywords: eIF2B; protein synthesis; ubiquitination; vanishing white matter