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Ap4A-RNA in IgE activated mast cells
Potužník, Jiří František ; Macíčková Cahová, Hana (advisor) ; Černý, Jan (referee)
Mast cells are tissue resident members of the immune system. They have a wide range of functions and receptors including the FcεRI receptor, which gets activated by binding to IgE bound to an antigen. When the cells are activated in this manner, a process termed the LysRS- Ap4A-MITF signalling pathway occurs, resulting in the translocation of the Lys tRNA synthetase into the nucleus and an activation of its moonlighting activity - the production of diadenosine tetraphosphate (Ap4A). Ap4A is a dinucleoside polyphosphate, a type of ubiquitous molecule present in all domains of life. They are made up of two nucleosides joined together by a 5' to 5' phosphodiester bridge of variable lengths. Recently, these molecules have been shown to serve as non-canonical initiating nucleotides during bacterial transcription, where they function as 5' RNA caps, similar to the well-known 7- methylguanosine eukaryotic mRNA cap. In this thesis, I present proof of existence of Ap 4A capped RNA in mast cells, a previously unknown 5' RNA structure in eukaryotic cells, and I attempt to pinpoint its role in the activation of these cells and in the wider context of mast cell mediated immune response. Keywords: mast cells, RNA caps, Dinucleoside polyphosphates, Ap 4A, RNA modification, IgE, FcεRI receptor, Lysine tRNA synthetase
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The function of 2'-O-methylated RNA in the context of viral infection
Potužník, Jiří ; Macíčková Cahová, Hana (advisor) ; Forstová, Jitka (referee)
RNA is subject to a wide array of post-transcriptional modifications. 2'-O-methylation is an essential intrinsic modification of RNA. It affects the structure and reactivity of the molecule as well as its function. 2'-O-methylation is highly conserved, present in all three domains of life. Viral RNA uses this modification to mimic the host and evade detection by the immune system. There are two main mechanisms, through which viral 2'-O-methylated RNA does this. The first is evading detection by a pattern recognition receptor form the RIG-I-like receptor family Mda5. Mda5 is capable of detecting unmethylated RNA and recognising it as non-self, thus initiating an immune response. The second mechanism the evasion and restriction of an effector molecule IFIT. IFIT proteins are capable of detecting the absence of 2'-O- methylation on viral RNAs and inhibiting their translation. They do this by interfering with the formation of the ternary complex, an essential member of ribosomal formation. Using viral 2'- O-methylation as a target for therapy, it is possible to develop attenuated vaccines. Keywords: viral RNA, RNA modifications, 2'-O-methylation, Mda5, IFIT, RIG-I-like receptors, epitranscriptomics, WNV, JEV
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