Di Monaco, Marisa (2020) Molecular mechanisms and transcriptional regulation of starvation induced autophagy in drosophila. PhD thesis, University of Warwick.

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Abstract

Autophagy is a fundamental and evolutionarily conserved process, in which cytoplasmic material is degraded through the lysosomal pathway. Nutrient deprivation is one of the main stresses known to induce autophagy and is tightly regulated by autophagic machinery. However, many of these mechanisms of regulation remain to be elucidated. One of the most well studied autophagy-related proteins is Atg8a (Drosophila homolog to mammalian LC3), which participates in autophagosome formation and autophagy cargo selection in the cytoplasm. Despite growing evidence that LC3/Atg8a is also enriched in the nucleus, mechanisms by which it is targeted to this compartment, and the nuclear components with which it interacts with remain poorly understood. Atg8-family interacting proteins have been shown to harbour a LC3-interacting region (LIR), which is highly conserved in Eukaryotes. Bioinformatical screening for this region has provided a gateway for the identification of Atg8a-interacting proteins. Here, a novel LIR containing nuclear protein, named Sequoia, is characterised.

Following the discovery of a LIR-dependent interaction between Atg8a and Sequoia, results presented here show that sequoia-depletion induces autophagy in nutrient-rich conditions through the enhanced expression of autophagy genes. Harbouring a zinc-finger binding domain, Sequoia is also found to bind to promoter regions of a wide set of autophagy genes, thereby repressing their transcriptional expression. Consistent with reports that indicate that the acetylation status of Atg8-family proteins is fundamental in their ability to interact with nuclear components, we piece together a mechanism of autophagic control within the nucleus by uncovering the roles of YL-1, a member of a component of a nuclear acetyltransferase complex, and deacetylase Sir2 (mammalian homolog SIRT1). Taken together, results here suggest a mechanism for the regulatory control of autophagy genes by transcription factor Sequoia and Atg8a, highlighting the importance of acetylation events in the induction of autophagy under starvation condition. Furthermore, we also uncover a potential role of dDOR (mammalian homolog DOR/ TP53INP2) and its ubiquitin-interacting motif in the cellular redistribution of Atg8a.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QL Zoology Q Science > QP Physiology
Library of Congress Subject Headings (LCSH):	Autophagic vacuoles, Drosophila melanogaster, Ubiquitin, Protein-protein interactions
Official Date:	October 2020
Dates:	Date Event October 2020 UNSPECIFIED
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:	pdf
Extent:	264 leaves : illustrations (some colour)
Language:	eng

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