Thesis supervisor: Milán Somogyvári
Location of studies (in Hungarian): Semmelweis Egyetem Abbreviation of location of studies: SE
Description of the research topic:
The Hsp90 heat-shock protein is an essential protein, required for the functionality of mammalian protein-protein and signaling networks, thus ensuring proper protein folding[1], intracellular transport[2], heterochromatin maintenance[3], protein degradation[4], telomere maintenance[5] and various aspects of cell signalling[6] in order to promote cellular growth and proliferation. In mammals and yeast the interaction network of Hsp90 is quite well known, hundreds of proteins stabilized by it have been described – like 60% of the human kinome[7]. In the nematode Caenorhabditis elegans – a widely used genetic model organism – Hsp90 has been linked to various phenotypic traits like chemosensory perception[8], larval development[9], vulval development[10], oogenesis[11], muscle function and motility[12] and cell non-autonomous regulation of proteostasis[13]. Its knockdown by RNAi or mutations results in various phenotypes like reduced apoptosis[14], bacterial lawn avoidance[15], defects in dauer phenotype formation and recovery[16], [17], larval arrest and disrupted gonad development[10], sterility[17], [18], defective immune response[19], as well as extended [20] or shortened[17], [20], [21] lifespan. In our previous studies we described Hsp90-dependent phenotypes like neuronally induced dauer formation, shortened lifespan and infertility[17], as well as SIR-2.1 being directly stabilized by Hsp90[22]. Despite the studies mentioned here, a comprehensive study on the interaction network of Hsp90 in C. elegans has not yet been carried out, and thus its interactome is still essentially unknown.
According to the working hypothesis of our project, determining the C.elegans Hsp90 interactome can not only shed light on the conformational evolution of the Hsp90 interactome and the proteins, strengthen the central role of the chaperone, but besides reinforcing interactions already known in mammals, it can also lead us to discoveries of new partners and biological functions. In this project we aim to map the interaction network of the C. elegans Hsp90 ortholog using a proximity labeling method under different circumstances. We plan to investigate the nature of the so identified new interactions and look for new biological functions with evolutionary or therapeutic relevance. Our experiments aim to answer the following questions:
• With which proteins does the C. elegans Hsp90 interact?
• What overlaps and differences can be recognized between the human and C. elegans Hsp90 interactome?
• How does the interactome change in response to various stresses?
• Are there tissue-specific peculiarities of this interaction network?
• What roles do Hsp90 and its clients play in the regulation of such physiological traits as lifespan, lipid metabolism, autophagy and possible new biological functions?
Our project is aiming to determine and characterize the first invertebrate multicellular Hsp90 interactome in a widely used developmental, aging, neurobehavioral model organism by an inducibly expressed[23], high precision proximity dependent biotinylation technique[24]. Through this, general conclusions can be made regarding the conformational evolution of proteins, the organization of the Hsp90 interactome, and the biological function of Hsp90. Investigation of the dynamics of the interaction network may shed light on stress-induced alterations, new treatment options and targets for protein homeostasis-related diseases such as neurodegenerative or metabolic diseases, and the side effects of therapies targeting Hsp90.
Deadline for application: 2024-06-30
2024. IV. 17. ODT ülés Az ODT következő ülésére 2024. június 14-én, pénteken 10.00 órakor kerül sor a Semmelweis Egyetem Szenátusi termében (Bp. Üllői út 26. I. emelet).
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