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Understanding the role of prion-like domains in ribonucleoprotein granule dynamics

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dc.contributor.authorBoncella, Amy Elizabeth, author
dc.contributor.authorRoss, Eric, advisor
dc.contributor.authorKennan, Alan, advisor
dc.contributor.authorPeersen, Olve, committee member
dc.contributor.authorAckerson, Chris, committee member
dc.date.accessioned2019-09-10T14:35:52Z
dc.date.available2019-09-10T14:35:52Z
dc.date.issued2019
dc.description.abstractRibonucleoprotein (RNP) granules are membraneless organelles, comprised of RNA-binding proteins and RNA, that are integrally related with the cellular stress response. Stress granules and processing bodies (p-bodies) are the two primary types of RNP granules that reversibly assemble upon stress. Interestingly, many of the proteins that localize to stress granules and p-bodies contain aggregation-prone prion-like domains (PrLDs). Furthermore, mutations in the PrLDs of a number of stress granule-associated proteins have been linked to various neurodegenerative diseases, leading to the idea that aggregation-promoting mutations in these PrLDs cause stress granule persistence. Altogether, these finding suggest an important role for these domains in the dynamics of these assemblies. In order to gain a greater understanding of how PrLDs contribute to RNP granule biology, I have taken two different approaches. The first was to investigate how aggregation-promoting mutations affect stress granule and p-body dynamics. I introduced various aggregation-promoting mutations into the PrLDs of different stress granule and p-body proteins and assessed the ability of these granules to disassemble, hypothesizing that these mutations would cause RNP granule persistence, as is observed in disease. Interestingly, despite successfully increasing the aggregation propensity of these PrLDs, stress granules and p-bodies do not persist and can efficiently disassemble after stress relief. Given that aggregation-promoting mutations in PrLDs of RNP granule proteins fail to cause granule persistence, I took a second, less targeted approach towards understanding the roles of these domains in RNP granules. I focused on investigating how PrLDs are recruited to RNP granules by screening a set of PrLDs for ability to assemble into foci upon stress. Interestingly, many PrLDs are sufficient to assemble into foci upon various stresses, with robust recruitment to stress granules upon heat shock. Furthermore, several compositional biases are observed among PrLDs that are and are not sufficient to assemble upon stress. Using these biases, we have developed a reasonably accurate composition-based predictor of PrLD recruitment into heat shock-induced stress granules, which has been further validated using rational mutation strategies. This predictor is reasonably successful at predicting whether a PrLD will assemble into stress granules upon stress. Additionally, scrambling of PrLD sequences does not disrupt recruitment to stress granules. Together, these results suggest that PrLD localization to stress granules is based on composition rather than primary sequence.
dc.format.mediumborn digital
dc.format.mediumdoctoral dissertations
dc.identifierBoncella_colostate_0053A_15558.pdf
dc.identifier.urihttps://hdl.handle.net/10217/197332
dc.languageEnglish
dc.language.isoeng
dc.publisherColorado State University. Libraries
dc.relation.ispartof2000-2019
dc.rightsCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.
dc.titleUnderstanding the role of prion-like domains in ribonucleoprotein granule dynamics
dc.typeText
dcterms.rights.dplaThis Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).
thesis.degree.disciplineChemistry
thesis.degree.grantorColorado State University
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)

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