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Title: Identification of novel IFITM1/IFITM3 signalling pathways implicated in the interferon response
Author: Gómez Herranz, Maria
ISNI:       0000 0004 8508 8581
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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Interferon induced transmembrane protein 1 (IFITM1) is an interferon (IFN) stimulated protein upregulated during development of radiation resistance in cancer. It is present in resistant tumours, generating a multi-drug resistant phenotype and escaping frompro-apoptotic effects (Weichselbaum et al., 2008a; Yang et al., 2007). The signal transduction events that are orchestrated by IFITM1/IFITM3 are not well defined. As IFITM1 is the main isoformdescribed as a pro-oncogene, we started studying its interactome. To begin to elucidate its molecular mechanism of action, isogenic IFITM1 null and IFITM1/IFITM3 double null cervical cancer cells, engineered by CRISPR/Cas9 system, were used to define dominant pathways mediated by IFITM1/IFITM3 proteins. The results suggested a specific role for IFITM1/IFITM3 in regulating ribosomal integrity. In this study, therefore, we explored whether IFITM1/IFITM3 were capable of facilitating protein synthesis. The localization of IFITM/IFITM3 to ribosomal translation protein factors prompted an analysis of IFN -dependent protein synthesis using pulse SILAC-mass spectrometry. The IFITM1/IFITM3-IFN complex mediates signal transduction through ISG15, IRF1, and HLA-B molecules. Additional experimental work consolidated the association between IFITM1/IFITM3 and HLA-B or ISG15. Moreover, the implications of IFITM1/IFITM3 loss of expression on RNA regulation were further investigated by RNASeq and RT-qPCR. In conclusion, the present study characterises a novel function for IFITM1/IFITM3 proteins. They are implicated in protein synthesis in IFN -stimulated cells, providing a new insight into how these proteins are relevant in cancer. These data have implications for the function of IFITM1/IFITM3 in mediating appropriate antigen presentation recognition and protein modification by ISGylation.
Supervisor: Hupp, Ted ; Arends, Mark Sponsor: Medical Research Council (MRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Interferon induced transmembrane proteins ; IFITM1 ; IFITM3