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Molecular mechanisms of selective autophagy in innate immunity
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Tsapras, Panagiotis (2021) Molecular mechanisms of selective autophagy in innate immunity. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3759973
Abstract
Selective autophagy is a catabolic route that engulfs cellular material on specialized vesicles called “autophagosomes” before turning them over to lysosomes for degradation. Such degradation substrates often interact and are anchored by the autophagosome-localized core autophagy protein LC3 (Atg8a in Drosophila). Autophagy is a pivotal process that helps in maintaining a homeostatic intracellular environment by contributing, among other functions, to the attenuation of innate immune signalling for several pathways, such as the IMD response in Drosophila. The IMD pathway, which this work focused on, is among the innate immune cascades that become increasingly harder to terminate with age; correlating with a concomitant waning of autophagy’s functions. The exact regulatory interactions between IMD pathway components and the autophagy machinery remain largely unknown.
This work identified that the apical kinase of the Drosophila IMD pathway, dTAK1, as well as its co-activator dTAB2, interact with the autophagy protein Atg8a as examined by GSTpulldown experiments and confocal microscopy colocalization studies. Furthermore, the interaction between dTAK1 and Atg8a seems to rely on the functional LIR motif harboured in the C-terminal of dTAK1, that binds its cognate LDS region on Atg8a. Observations from qPCR assays that were employed to measure mRNA expression levels of the IMD-regulated genes AttA, DptB and Dro in conventionally reared young and old adult flies, suggest that the dTAK1 LIR motif prevents at least partly, the chronic overactivation of the IMD pathway. This study also further delineates the role of the Atg8a-interacting protein SH3PX1 in downregulating the IMD pathway, by characterizing the interaction between dTAB2 and SH3PX1, assessed by mass-spectroscopy and GST pulldown experiments. Genetic ablation of Sh3px1 correlates with both, increased levels of AttA, DptB and Dro that suggest overactivation of the IMD pathway in young and old Sh3px1-deficient flies, as well as their overall markedly reduced lifespan compared to controls in survival assays.
Based on the insight gleaned by this study, I propose a mechanistic model for the dTAK1/dTAB2/SH3PX1 interactions with Atg8a, which may collectively mediate the selective autophagic degradation of the dTAK1/dTAB2 complex, and prevent in turn the constitutive activation of the IMD pathway in Drosophila. The conservation of all components in mammals provides encouraging evidence for potential similarities with the human condition as well.
| Item Type: | Thesis (PhD) | ||||
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| Subjects: | Q Science > QH Natural history Q Science > QR Microbiology > QR180 Immunology |
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| Library of Congress Subject Headings (LCSH): | Autophagic vacuoles, Cellular immunity, Immune response -- Molecular aspects, Homeostasis, Drosophila, Cellular control mechanisms | ||||
| Official Date: | May 2021 | ||||
| Dates: |
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| Institution: | University of Warwick | ||||
| Theses Department: | School of Life Sciences | ||||
| Thesis Type: | PhD | ||||
| Publication Status: | Unpublished | ||||
| Supervisor(s)/Advisor: | Nezis, Ioannis P. | ||||
| Format of File: | |||||
| Extent: | xii, 237 leaves : illustrations | ||||
| Language: | eng |
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