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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Exploring HMGB1 protein-protein interactions in the monocytic cell lineage THP-1.

Tsang, Choi January 2022 (has links)
High mobility group box 1 (HMGB1) was first identified as a chromatin-associated protein and later discovered to initiate and regulate inflammation by inducing cytokine production, cell migration and cell differentiation. HMGB1 forms complexes with a variety of proteins (e.g. C1q, LPS, CXCL12, IL-1a, IL1b, Beclin-6, p53) that in turn play a role in different cellular mechanisms. However, most HMGB1-protein complexes identified are found in the extracellular space whereas intracellular HMGB1-protein complexes are far less defined.  Firstly, data of HMGB1 interactome was previously generated by Rebecka Heinbäck, Erlandsson Harris group at KI. The HMGB1 interactome was identified in resting and in LPS-stressed THP-1 cells using a method called BioID.  The objective was to explore possible intracellular HMGB1 protein-protein interactions during resting and inflammatory conditions. HMGB1 in complex with other proteins have been known to exhibit crucial functions, therefore our investigation can lead to important knowledge in developing promising future therapeutics targeting HMGB1 in addition to further knowledge on intracellular functions of HMGB1. In this project, we used a combination of different computational analysis tools to explore the roles of HMGB1 and its interactome. Thereafter, we selected proteins within the BioID dataset that were further investigated for direct protein-protein interactions with HMGB1 using computational modelling as well as laboratory techniques, such as co-immunoprecipitation.  Our data reveals functional and biological differences of HMGB1 in resting and LPS activated THP-1 cells. Within resting cells, the HMGB1 interactome is involved in transduction and transcription processes whereas under LPS-stressed conditions HMGB1 is indicated in apoptosis, HATs, and processes in antiviral mechanisms, mainly when localised in the cytosol. Additionally, we revealed potential direct interaction of HMGB1 to S100A6 and HCLS1, in which both can induce different functionalities. Finally, we have further explored the interaction possibilities of HMGB1:S100A6 complex to RAGE, where we found interesting, preliminary results that should be further explored.  To conclude, this thesis suggests new direct, intracellular interaction partners to HMGB1 and indicates a shift in the HMGB1 interactome following LPS stress.

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