자료유형  

 학위논문

Control Number  

0017164522

International Standard Book Number  

9798384045090

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Metur, Shree Padma.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of Michigan., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

223 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-03, Section: B.

General Note  

Advisor: Klionsky, Daniel J.

Dissertation Note  

Thesis (Ph.D.)--University of Michigan, 2024.

Summary, Etc.  

요약Macroautophagy/autophagy is a conserved, eukaryotic, highly regulated cellular degradative process that removes superfluous cytoplasmic components and damaged organelles in either non-selective or selective manner. Autophagy occurs at the basal level in almost all cells to ensure homeostatic removal of cytoplasmic components, however, it is significantly upregulated in response to stressful conditions such as nutrient starvation. For the appropriate induction and execution of the process, the coordinated function of several autophagy proteins is required. However, during nutrient starvation, global translation is downregulated to conserve essential metabolic reserves such as nucleotides and amino acids. Therefore, an important question arises, how does the cell selectively upregulate the translation of autophagy related (ATG) genes in response to nutrient starvation?Protein synthesis is controlled by post-transcriptional mechanisms influenced by RNA-binding proteins. The localization, stability and translational efficiency is controlled by RNA-binding proteins that target specific mRNAs. In order the understand the mechanisms of posttranscriptional control of autophagy, in this dissertation, I focus on ATG1 mRNA that encodes for an important kinase required for autophagy induction, Atg1. I ask if there are specific protein marks that prime ATG1 transcript for translation during nitrogen starvation.Towards this, in Chapter 2, I develop an in vitro assay using labeled mRNA to specifically identify RNA-binding proteins that bind to ATG1 5' and 3' untranslated regions (UTRs). Through this method, I identify Npl3 and Pub1 as positive regulators of autophagy that targets 5' and 3' UTR of ATG1 respectively. Further analyses into the role of Npl3 and Pub1 revealed that Npl3 "imprints" ATG1 transcript with Pub1 in the nucleus. Pub1, subsequently, facilitates export of ATG1 transcript to the cytoplasm and recruits translational factors and ribosome components to enhance translation of Atg1. Intriguingly, in non-small cell lung cancer cells, the mammalian homolog pf Pub1, TIA1, regulates the expression of ULK1, the mammalian counterpart of Atg1, at the post-transcriptional level, thereby positively upregulating autophagy.In Chapter 3, I explore the differential regulation of autophagy in yeast in response to two different nutrient states: nitrogen starvation and amino acid starvation. I discover that the differential regulation occurs at the level of post-transcriptional regulation of the ATG1 transcript. Utilizing the approach developed in Chapter 2, I discovered that Ded1 is a nutrient responsive regulator of ATG1 regulation. Further investigation revealed that its upstream kinase Rad53 selectively enhances ATG1 and Ded1 interaction to facilitate the translational upregulation of Atg1. Additionally, I demonstrate that ULK1 undergoes similar post-transcriptional regulation by DDX3, the mammalian homolog of Ded1, highlighting the conservation of this regulatory mechanism.In summary, this dissertation, uncovers novel post-transcriptional regulatory mechanisms of autophagy. I develop a high-throughput methodology to identify RNA-binding proteins that specifically bind to a transcript, especially ATG1. I identify novel and conserved regulators of autophagy, Npl3 and Pub1. Finally, this dissertation expands the repertoire of autophagy regulators with potential clinical benefit.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Molecular biology.

Subject Added Entry-Topical Term  

Biochemistry.

Subject Added Entry-Topical Term  

Developmental biology.

Index Term-Uncontrolled  

Autophagy

Index Term-Uncontrolled  

Translational regulation

Index Term-Uncontrolled  

RNA binding proteins

Index Term-Uncontrolled  

Messenger RNA

Index Term-Uncontrolled  

Nutrient

Added Entry-Corporate Name  

University of Michigan Molecular Cellular and Developmental Biology

Host Item Entry  

Dissertations Abstracts International. 86-03B.

Electronic Location and Access  

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Control Number  

joongbu:654979