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TMEM203 is a putative co-receptor of innate immune adaptor protein STING

Li, Yang (2019) TMEM203 is a putative co-receptor of innate immune adaptor protein STING. PhD thesis, University of Sheffield.

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2019.07.09 Thesis final corrected.pdf
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Abstract

Acute inflammation is the innate immune defence against environmental disturbances. Macrophages are one of the central immune cells that react to infections and maintain tissue homeostasis, and they exhibit their functions via numerous inflammatory signalling regulators. In addition to previously identified immune mediators, novel proteins involved in inflammation continue to emerge. A previous cDNA functional screening in murine macrophages has identified a novel protein named transmembrane protein 203 (Tmem203) displaying pro-inflammatory characteristics. Tmem203-promoted inflammatory activities were found to be TLR independent but dependent on STING, a cytosolic innate immune adaptor for DNA detection. STING responds to upstream DNA sensors and microbial cyclic dinucleotides, and instigates type I interferon response via TBK1-IRF3 axis. The work in this thesis investigated the function of TMEM203 in STING-dependent type I interferon responses. TMEM203 has been found to colocalise, interact and migrate with STING. Further studies revealed a critical role for TMEM203 in STING-dependent type I interferon response in both human and mouse primary macrophages. We showed that TMEM203-STING association was highly dependent on STING’s N-terminal transmembrane domains. Finally, TMEM203 showed a distinct regulation of STING-interferon signalling between stimulation by natural and synthetic STING ligands, and this difference was also reflected in TMEM203-STING interaction. Thus, this novel mechanism of TMEM203-dependent STING regulation has brought new insights to better understand critical regulators of pathogen infections and interferon-associated autoimmune diseases. Additionally, a brief research was conducted to explore STING regulation in flavivirus infected primary macrophages. Flaviviruses Dengue virus and Zika virus infect humans to cause global pandemics. Dengue virus is known to specifically and potently interrupt STING-interferon pathway. The emerging flavivirus Zika virus is genetically-closely related to Dengue virus and thus it has been hypothesised to adopt similar strategies in STING antagonism. We have investigated Dengue and Zika virus-induced type I interferon stimulated ISG response in the M-CSF differentiated primary macrophage model, and tested the role of STING in such conditions. Contradictory to previous report, our experiments showed a potent and persistent ISG induction in virus-infected macrophages. Prior virus infections were unable to intercept ISG induction cause by STING ligands, whereas the downregulation of STING dampens virus-induced ISG response. Therefore, this primary macrophage model highlights alternative regulatory mechanisms via STING in response to Dengue and Zika virus.

Item Type: Thesis (PhD)
Keywords: TMEM203, STING, interferon, inflammation, immunity, Dengue, Zika
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield)
The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Depositing User: Dr Yang Li
Date Deposited: 22 Jul 2019 10:07
Last Modified: 31 Jul 2020 00:18
URI: http://etheses.whiterose.ac.uk/id/eprint/24440

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