Novel Protein Regulators of Heat Shock Transcription Factor 1 During Stress and Disease

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2019

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Abstract

Heat Shock Transcription Factor 1 (HSF1) is a critical regulator of transcription that facilitates cellular stress protection in response to protein misfolding, rapid cell proliferation, and other stressful conditions. Defective HSF1 regulation is observed in cellular and animal models of cancer, where hyperactive and dysregulated HSF1 supports cancer survival, and in neurodegenerative disease, where HSF1 function is compromised, further exacerbating protein misfolding. HSF1 is tightly regulated through intramolecular interactions, post-translational modifications, and protein-protein interactions; however, little is known about ho HSF1 regulation differs in response to stresses such as acute or chronic protein misfolding.

We identified one mechanism that contributes to the diminution of HSF1 in chronic protein misfolding in the context of Huntington’s Disease involving inappropriate interactions of HSF1 with CK2α’ and FBXW7 E3 ligase. We found these protein-protein interactions coordinate the abnormal phosphorylation-dependent degradation of HSF1. Importantly, inhibition of this aberrant HSF1 degradation attenuates the biochemical defects and protein misfolding in Huntington’s Disease. To further elucidate how HSF1-interacting proteins regulate HSF1 in acute and chronic stress, we carried out quantitative proteomics studies of the HSF1 interactome under control, acute heat shock, and in a cell model of Huntington’s Disease. We recapitulated many previously described interaction partners of HSF1 and identified several novel HSF1-interacting proteins that encompass a wide variety of cellular functions, including roles in DNA repair, mRNA processing, and regulation of RNA polymerase II. We further report on the interaction of HSF1 with CCCTC binding factor (CTCF), which modulates target gene activation and repression function of HSF1 by facilitating DNA binding at CTCF and HSF1 co-regulated loci. Given the role and elevated expression of both pro-inflammatory proteins and Tau in Huntington’s Disease, and their defective repression by HSF1, understanding the mechanisms of HSF1 repression is of great interest. The studies presented in this thesis expand our understanding of HSF1-mediated gene activation and repression, and the regulation of HSF1 via protein-protein interactions.

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Burchfiel, Eileen Therese Malloy (2019). Novel Protein Regulators of Heat Shock Transcription Factor 1 During Stress and Disease. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/19881.

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