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Nuclear targeting of Hsp110 modifies the proteostasis system by mobilizing latent Hsp70 chaperones
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.ORCID-id: 0000-0001-8948-0685
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Biokemi och molekylärbiologi Cellbiologi
Forskningsämne
molekylär biovetenskap
Identifikatorer
URN: urn:nbn:se:su:diva-148368OAI: oai:DiVA.org:su-148368DiVA, id: diva2:1151410
Tillgänglig från: 2017-10-23 Skapad: 2017-10-23 Senast uppdaterad: 2020-03-04Bibliografiskt granskad
Ingår i avhandling
1. Regulation of cellular Hsp70: Proteostasis and aggregate management
Öppna denna publikation i ny flik eller fönster >>Regulation of cellular Hsp70: Proteostasis and aggregate management
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Proteins have to be folded to their native structures to be functionally expressed. Misfolded proteins are proteotoxic and negatively impact on cellular fitness. To maintain the proteome functional proteins are under the constant surveillance of dedicated molecular chaperones that perform protein quality control (PQC). Using the model organism yeast Saccharomyces cerevisiae this thesis investigates the molecular mechanisms that cells employ to maintain protein homeostasis (proteostasis). In Study I the role of the molecular chaperone Hsp110 in the disentanglement and reactivation of aggregated proteins was investigated. We found that Hsp110 is essential for cellular protein disaggregation driven by the molecular chaperones Hsp40, Hsp70 and Hsp104 and characterized its involvement via regulation of Hsp70 ATPase activity as a nucleotide exchange factor. In Study II we found out that Hsp110 undergoes translational frameshifting during its expression resulting in a nuclear targeting. Nuclear Hsp110 interacts with Hsp70 and reprograms the proteostasis system to better deal with stress and to confer longevity. Study III describes regulation of Hsp70 function in PQC by the nucleotide exchange factor Fes1. We found that rare alternative splicing regulates Fes1 subcellular localization in the cytosol and nucleus and that the cytosolic isoform has a key role in PQC. In Study IV we have revealed the molecular mechanism that Fes1 employ in PQC. We show that Fes1 carries a specialized release domain (RD) that ensures the efficient release of protein substrates from Hsp70, explaining how Fes1 maintains the Hsp70-chaperone system clear of persistent misfolded proteins. In Study V we report on the use of a novel bioluminescent reporter (Nanoluc) for use in yeast to measure the gene expression and protein levels. In summary, this thesis contributes to the molecular understanding of chaperone-dependent PQC mechanisms both at the level of individual components as well as how they interact to ensure proteostasis.

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2017
Nationell ämneskategori
Biokemi och molekylärbiologi Cellbiologi
Forskningsämne
molekylär biovetenskap
Identifikatorer
urn:nbn:se:su:diva-148410 (URN)978-91-7649-998-6 (ISBN)978-91-7649-999-3 (ISBN)
Disputation
2017-12-08, E306, Arrheniuslaboratorierna, Svante Arrhenius väg 20 C, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Anmärkning

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript.

Tillgänglig från: 2017-11-15 Skapad: 2017-10-24 Senast uppdaterad: 2020-05-07Bibliografiskt granskad

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Av författaren/redaktören
Kaimal, Jayasankar MohanakrishnanHabernig, LukasBüttner, SabrinaAndréasson, Claes
Av organisationen
Institutionen för molekylär biovetenskap, Wenner-Grens institut
Biokemi och molekylärbiologiCellbiologi

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