title: Cytosolic splice isoform of Hsp70 nucleotide exchange factor Fes1 is required for the degradation of misfolded proteins in yeast.
abstract: Cells maintain proteostasis by selectively recognizing and targeting misfolded proteins for degradation. InSaccharomyces cerevisiae, the Hsp70 nucleotide exchange factor Fes1 is essential for the degradation of chaperone-associated misfolded proteins by the ubiquitin-proteasome system. Here we show that theFES1transcript undergoes unique 3' alternative splicing that results in two equally active isoforms with alternative C-termini, Fes1L and Fes1S. Fes1L is actively targeted to the nucleus and represents the first identified nuclear Hsp70 nucleotide exchange factor. In contrast, Fes1S localizes to the cytosol and is essential to maintain proteostasis. In the absence of Fes1S, the heat-shock response is constitutively induced at normally nonstressful conditions. Moreover, cells display severe growth defects when elevated temperatures, amino acid analogues, or the ectopic expression of misfolded proteins, induce protein misfolding. Importantly, misfolded proteins are not targeted for degradation by the ubiquitin-proteasome system. These observations support the notion that cytosolic Fes1S maintains proteostasis by supporting the removal of toxic misfolded proteins by proteasomal degradation. This study provides key findings for the understanding of the organization of protein quality control mechanisms in the cytosol and nucleus.
authors.affiliation: Department of Molecular Biosciences, Stockholm University, S-10691 Stockholm, Sweden.
authors.forename: Naveen Kumar Chandappa
authors.initials: NK
authors.lastname: Gowda
authors.affiliation: Department of Molecular Biosciences, Stockholm University, S-10691 Stockholm, Sweden.
authors.forename: Jayasankar Mohanakrishnan
authors.initials: JM
authors.lastname: Kaimal
authors.affiliation: Department of Molecular Biosciences, Stockholm University, S-10691 Stockholm, Sweden.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Masser
authors.affiliation: Science for Life Laboratory, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-10691 Stockholm, Sweden.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Kang
authors.affiliation: Science for Life Laboratory, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-10691 Stockholm, Sweden.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Friedländer
authors.affiliation: Department of Molecular Biosciences, Stockholm University, S-10691 Stockholm, Sweden claes.andreasson@su.se.
authors.forename: Claes
authors.initials: C
authors.lastname: Andréasson
mesh_terms: D017398:Alternative Splicing; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D007438:Introns; D049409:Luciferases, Firefly / Q000737:chemistry / Q000378:metabolism; D026723:Polyadenylation; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D020033:Protein Isoforms; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: C507801:FES1 protein, S cerevisiae; D018840:HSP70 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; D049409:Luciferases, Firefly; D046988:Proteasome Endopeptidase Complex