자료유형  

 학위논문

Control Number  

0017164377

International Standard Book Number  

9798384042334

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Knupp, Jeffrey R.

Publication, Distribution, etc. (Imprint  

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

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

177 p.

General Note  

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

General Note  

Advisor: Tsai, Billy.

Dissertation Note  

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

Summary, Etc.  

요약The endoplasmic reticulum (ER) is an expansive and dynamic organelle that regulates numerous cellular functions, including the macro-autophagy pathway (hereby referred to as autophagy). During autophagy, cells target their components to the lysosome for degradation and recycling into macromolecules that can be repurposed. At the ER, autophagy is initiated by the formation of a structure called the "omegasome," which serves as a platform for autophagy-regulating proteins, including the critical autophagy protein LC3. LC3 is lipidated at the omegasome, and this lipidated LC3 is the functionally active form. How LC3 is recruited to ER-localized omegasomes is unclear. This dissertation revealed that the ER membrane protein Sigma 1 non-opioid intracellular receptor 1 (S1R) recruits LC3 to ER-associated omegasomes via a unique mechanism: S1R binds directly to the 3'UTR of LC3 mRNA which targets this transcript to the ER, thereby enabling ER-localized translation of LC3 where this protein functions. Targeted translation of LC3 is required for proper lipidation of LC3, which explains the practical reason for this mechanism. Beyond its role in autophagy initiation, the ER also functions in a selective form of autophagy termed "ER-phagy." During ER-phagy, sections of the ER containing misfolded or aggregated proteins are routed to lysosomes for degradation, thereby supporting ER proteostasis. This work identified that a mutant proinsulin - known to causes diabetes - is recruited into the ER-phagy pathway by engaging an ER membrane protein called PGRMC1. Mechanistically, PGRMC1-bound mutant proinsulin is recruited to select sites in the ER that are in turn fragmented and targeted to the lysosome for degradation. In this manner, PGRMC1 acts as a cargo receptor for ER-phagy of mutant proinsulin, as well as for other mutant prohormones that misfold in the ER lumen and cause metabolic diseases. In sum, this dissertation uncovers the role of two ER transmembrane proteins that regulate 1) ER-initiated autophagy for recycling of macromolecules (S1R), and 2) how misfolded proteins within the ER lumen can be targeted to the lysosome for degradation (PGRMC1).

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Biochemistry.

Subject Added Entry-Topical Term  

Molecular chemistry.

Index Term-Uncontrolled  

Autophagy

Index Term-Uncontrolled  

Endoplasmic reticulum

Index Term-Uncontrolled  

Protein quality control

Added Entry-Corporate Name  

University of Michigan Cellular & Molecular Biology

Host Item Entry  

Dissertations Abstracts International. 86-03B.

Electronic Location and Access  

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Control Number  

joongbu:657066