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Title: Defining Viral Strategies for Remodeling Organelle Structure and Function
Authors: Cook, Katelyn Camille
Advisors: Cristea, Ileana M
Contributors: Molecular Biology Department
Keywords: membrane contacts
Subjects: Molecular biology
Cellular biology
Issue Date: 2022
Publisher: Princeton, NJ : Princeton University
Abstract: Eukaryotic cells partition biological processes into subcellular compartments known as organelles. Each organelle is composed of specific proteins, lipids, and small molecules that determine a specialized structure, in turn dictating organelle functions. Regulating organelle structure-function relationships is fundamental to cellular viability, whereby cells finely-tune organelle composition to alter structure and enhance specific functions for maintaining homeostasis. The importance of organelle remodeling is well-illustrated during the progression of human virus infections. Organelles underlie the ability of host cells to detect and combat pathogen invasion. Likewise, viruses are obligate intracellular parasites and rely on the biological machinery partitioned within organelles to replicate, assemble, and spread progeny virions. Viruses can reprogram organelles from pro-host to pro-viral states on short replication timescales and with limited gene products. Infection-induced changes to organelle functions often coincide with modulation of organelle dynamics: morphology, composition, localization, and biogenesis. However, the links between viral alterations to organelle dynamics and downstream functional outputs are poorly understood, and the molecular underpinnings of virus-driven organelle remodeling events remain largely unknown. Integrating approaches from proteomics to super-resolution microscopy, I have explored viral strategies for remodeling organelles across subcellular space and infection time. We uncovered the multi-faceted rewiring of peroxisomes during herpesvirus infections, showing that increased peroxisome numbers, proteomes, and size enhance plasmalogen lipid synthesis for virus assembly. Further investigation of both peroxisomes and mitochondria during human cytomegalovirus (HCMV) infection revealed time-sensitive virus-host protein interactions with integral organelle structural proteins, such as the MICOS complex and peroxisome fission machinery. Finally, we explored the contribution of organelle membrane contact sites to infections with both ancient (HCMV, herpes simplex virus type 1) and rapidly-evolving (influenza A, beta-coronavirus OC43) human viruses. Our findings demonstrate dynamic, virus-driven alterations to the protein levels, tethering interactions, and sub-organelle localizations that govern these nanometer-scale organelle junctions, enabling a global coordination of organelle rewiring for virus production. We also discovered an asymmetric mitochondria-ER encapsulation structure (MENC) and showed that ER-mediated contacts underlie pro-viral peroxisome restructuring during HCMV infection. These organelle remodeling events offer molecular fingerprints of infection progression, furthering our understanding of how viruses manipulate cellular organization to subvert host cell biology.
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Molecular Biology

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