자료유형  

 학위논문

Control Number  

0017161439

International Standard Book Number  

9798382812540

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Steinbach, Adriana.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of California, San Francisco., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

87 p.

General Note  

Source: Dissertations Abstracts International, Volume: 85-12, Section: B.

General Note  

Advisor: Dumont, Sophie.

Dissertation Note  

Thesis (Ph.D.)--University of California, San Francisco, 2024.

Summary, Etc.  

요약Intracellular bacterial pathogens have evolved to survive in a distinctly hostile environment. Intravacuolar pathogens such as Legionella pneumophila (L.p.) reside within a membrane-bound compartment in their host cell, reshaping host materials into a new, protected organelle. The molecular mechanisms employed by L.p. during early infection to defend its vacuole are not entirely understood. As host cells uptake the bacterium by phagocytosis, L.p. must avoid classical trafficking of its phagosome through the endolysosomal pathway and attack by autophagy, which would ultimately lead to destruction of the bacterium in the lysosome. In this work, we set out to define how L.p. manipulates host regulatory proteins to defend its vacuole, termed the Legionella-containing vacuole (LCV), from these threats during early infection. First, we explore the interaction of the host small GTPase Rab5 with the LCV. Rab5 is the master regulator of the early endosomal compartment and is required for phagosome maturation. We determine that Rab5 associates with the LCV and is both mono- and polyubiquitinated during infection. This ubiquitination is dependent on two groups of secreted bacterial effector proteins: SidC/SdcA and the SidE family. SidC/SdcA are required for both mono- and polyubiquitination of Rab5, whereas the SidE family is largely responsible for polyubiquitination. We find that SidE family-dependent polyubiquitination is necessary for retention of Rab5 at the LCV membrane. Next, we recognized that Rab5 presents a unique experimental opportunity to study how host proteins are modified by effectors at the LCV, as Rab5 localizes to both the WT and avirulent strain LCV. We determine that Rab5 associated with the WT LCV has exceptionally high stability and a distinctive morphology dependent on the SidE family of effectors rather than host regulators. Finally, we discover that L.p. infection induces a burst of ubiquitination of both host and bacterial proteins and that SidC/SdcA are likely required for this burst. We propose a new role for SidC/SdcA as metaeffectors, regulating the activity of other as yet unknown bacterial proteins. Taken together, our findings suggest a model in which L.p. uses ubiquitin as a tool to retain and stabilize proteins at the LCV membrane, perhaps playing a role in containment of deleterious host proteins or participating in a physical blockade around the vacuole. This work illustrates the complex interplay between two fascinating families of L.p. effectors and refines our understanding of the strategies utilized by L.p to protect its vacuole during early infection.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Microbiology.

Subject Added Entry-Topical Term  

Pathology.

Index Term-Uncontrolled  

Endolysosomal biology

Index Term-Uncontrolled  

Host-pathogen interactions

Index Term-Uncontrolled  

Legionella pneumophila

Index Term-Uncontrolled  

Ubiquitin

Added Entry-Corporate Name  

University of California, San Francisco Cell Biology

Host Item Entry  

Dissertations Abstracts International. 85-12B.

Electronic Location and Access  

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Control Number  

joongbu:658027