title: Int6 and Moe1 interact with Cdc48 to regulate ERAD and proper chromosome segregation.
abstract: Int6/eIF3e is implicated in tumorigenesis, but its molecular functions remain unclear. We have studied its fission yeast homolog Yin6, reporting that it regulates proteolysis by controlling the assembly/localization of proteasomes, and binds directly to another conserved protein, Moe1. In the present study, we isolated Cdc48 as a Moe1-binding protein from a yeast two-hybrid screen, and confirmed biochemically that they form a stable complex in fission yeast. Overexpressing Moe1 or Yin6 partially rescued phenotypes of cdc48 mutants; conversely, overexpressing Cdc48 partially rescued phenotypes of moe1 or yin6 mutants. Mutants defective in both Cdc48 and the Yin6-Moe1 complex showed growth defects that were far more severe than either alone. These double mutants were severely deficient in endoplasmic reticulum associated degradation (ERAD), as they were hypersensitive to accumulation of misfolded proteins. In addition, their chromosomes showed frequent defects in spindle attachment and segregation--these mitotic defects correlated with Ase1 and Bir1/survivin mislocalization. These results suggest that Cdc48, Yin6 and Moe1 act in the same protein complex to concertedly control ERAD and chromosome segregation. Many of these properties are evolutionarily conserved in humans, since human Cdc48 rescued the lethality of the yeast cdc48Delta mutant, and Int6 and Moe1/eIF3d bind Cdc48 in human cells.
authors.affiliation: Interdepartmental Program in Cell and Molecular Biology, and Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Joel H
authors.initials: JH
authors.lastname: Otero
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Suo
authors.forename: Colin
authors.initials: C
authors.lastname: Gordon
authors.forename: Eric C
authors.initials: EC
authors.lastname: Chang
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D026481:Blotting, Far-Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D020090:Chromosome Segregation / Q000235:genetics / Q000502:physiology*; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D011485:Protein Binding / Q000502:physiology; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D000074405:Valosin Containing Protein
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D039642:Eukaryotic Initiation Factors; C117671:Moe1 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; C419775:int6 protein, S pombe; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein