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Title: Investigating the role of the non-canonical inflammasome in senescence
Author: Fernández Duran, Irene
ISNI:       0000 0004 8498 0164
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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Cellular senescence is a permanent proliferative arrest of cells triggered by several different stress mechanisms. Senescent cells display an inflammatory phenotype termed the senescence-associated secretory phenotype (SASP), being IL-1 signalling one of its key signalling pathways. Full-length IL-1b is cleaved into its mature active form by caspase-1, core enzymatic protein of a cytosolic platform called the canonical inflammasome. In contrast, caspase-4, central to the non-canonical inflammasome by analogy, can not cleave IL-1b although it can regulate canonical inflammasome activity. Moreover, research findings in recent years have revealed that inflammatory caspases (i. e. caspase- 1 and caspase-4) are key mediators of a type of inflammatory cell death called pyroptosis. Although caspase-1 and 4 are crucial in inflammatory responses, the function of inflammatory caspases in senescence remained poorly studied. Thus, this research thesis was conducted to investigate the role of inflammatory caspases in oncogene-induced senescence (OIS). Caspase-4 expression was observed to be increased in RASG12V-induced senescence in human primary IMR90 fibroblasts. Depletion of caspase-4 in this model of OIS impacted on the inflammatory signature (including reduced expression of SASP members and regulation of IL-1b) as well as a partial bypass of the proliferation arrest. Activation of caspase-4 by intracellular lipopolysaccharide (LPS) induced not only cell death by pyroptosis but also a senescence phenotype in the fraction of cells surviving cell death. Finally, a protein-protein interaction study by a proximity biotinylation approach followed by mass spectrometry analysis was conducted to unravel potential interactors of inflammatory caspases in OIS. In all, this thesis describes a novel role for caspase-4 in senescence.
Supervisor: Acosta, Juan Carlos ; Christophorou, Maria Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: caspase-4 ; non-canonical inflammasome ; senescence ; Senescence-associated Secretory Phenotype ; oncogene-induced senescence ; inflammatory caspases