title: Cytosolic chaperones mediate quality control of higher-order septin assembly in budding yeast.
abstract: Septin hetero-oligomers polymerize into cytoskeletal filaments with essential functions in many eukaryotic cell types. Mutations within the oligomerization interface that encompasses the GTP-binding pocket of a septin (its "G interface") cause thermoinstability of yeast septin hetero-oligomer assembly, and human disease. When coexpressed with its wild-type counterpart, a G interface mutant is excluded from septin filaments, even at moderate temperatures. We show that this quality control mechanism is specific to G interface mutants, operates during de novo septin hetero-oligomer assembly, and requires specific cytosolic chaperones. Chaperone overexpression lowers the temperature permissive for proliferation of cells expressing a G interface mutant as the sole source of a given septin. Mutations that perturb the septin G interface retard release from these chaperones, imposing a kinetic delay on the availability of nascent septin molecules for higher-order assembly. Un-expectedly, the disaggregase Hsp104 contributes to this delay in a manner that does not require its "unfoldase" activity, indicating a latent "holdase" activity toward mutant septins. These findings provide new roles for chaperone-mediated kinetic partitioning of non-native proteins and may help explain the etiology of septin-linked human diseases.
authors: Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors: Courtney R
authors: CR
authors: Johnson
authors: Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors: Andrew D
authors: AD
authors: Weems
authors: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720.
authors: Jennifer M
authors: JM
authors: Brewer
authors: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720.
authors: Jeremy
authors: J
authors: Thorner
authors: Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 Michael.McMurray@ucdenver.edu.
authors: Michael A
authors: MA
authors: McMurray
mesh_terms: D000483:Alleles; D003599:Cytoskeleton / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D055503:Protein Multimerization; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D058112:Septins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins; C070319:YDJ1 protein, S cerevisiae; C070972:HsP104 protein, S cerevisiae; D058112:Septins