Graduation Year


Document Type




Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Biology (Cell Biology, Microbiology, Molecular Biology)

Major Professor

Sandy D. Westerheide, Ph.D.

Committee Member

Meera Nanjundan, Ph.D.

Committee Member

Younghoon Kee, Ph.D.

Committee Member

Eric Guisbert, Ph.D.


aging, C. elegans, HSF-1, PTMs


The decline of proteostasis is a hallmark of aging that is, in part, affected by the dysregulation of the heat shock response (HSR), a highly conserved cellular response to proteotoxic stress in the cell. The heat shock transcription factor HSF-1 is well-studied as a key regulator of proteostasis, but mechanisms that could be used to modulate HSF-1 function to enhance proteostasis during aging are largely unknown. In this study, we examined lysine acetyltransferase regulation of the HSR and HSF-1 in C. elegans. We performed an RNA interference screen of lysine acetyltransferases and examined mRNA expression of the heat-shock inducible gene hsp-16.2, a widely used marker for HSR activation. From this screen, we identified one acetyltransferase, CBP-1, the C. elegans homolog of mammalian CREB-binding protein CBP/p300, as a negative regulator of the HSR. We found that while knockdown of CBP-1 decreases the overall lifespan of the worm, it also enhances heat shock protein production upon heat shock and increases thermotolerance of the worm in an HSF-1 dependent manner. Similarly, we examined a hallmark of HSF-1 activation, the formation of nuclear stress bodies (nSBs). In analyzing the recovery rate of nSBs, we found that knockdown of CBP-1 enhanced the recovery and resolution of nSBs after stress. Collectively, our studies demonstrate a role of CBP-1 as a negative regulator of HSF-1 activity and its physiological effects at the organismal level upon stress.

Defects in proteostasis that occur with aging are also central to many human diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. These neurodegenerative diseases (NDDs) are proteotoxic diseases hallmarked by increased protein misfolding and aggregation. Many components of the heat shock response are downregulated in NDD and aging, including HSF1. The regulation of HSF-1 in neurodegenerative diseases has yet to be fully elucidated. Thus, we examined regulation of HSF1 and its target genes in NDD models in C. elegans. We found that hsf-1 expression is decreased in an Alzheimer’s disease model expressing human amyloid-β1-42 (Aβ). In contrast, we found that the presence of Aβ increased the expression of heat shock inducible HSF-1 target genes hsp-16.2 and hsp-70. To further examine the relationship between HSF-1 and Aβ, we utilized an endogenous HSF-1::GFP worm strain previously made in the lab that we then crossed with the Aβ model of Alzheimer’s disease to visualize tissue-specific HSF-1 expression in the disease state and with age. We visualized HSF-1::GFP foci in multiple tissue types in the Aβ background. Collectively, these findings begin uncovering the regulation of HSF-1 and the heat shock response in neurodegenerative disease in C. elegans.

Lastly, the mechanism of HSF1 degradation in general, and in neurodegenerative disease in particular, is not thoroughly characterized. Recent studies have identified two E3 ubiquitin ligases, FBXW7 and NEDD4, that target HSF1 for degradation in Huntington’s and Parkinson’s disease, respectively. Our goal is to further elucidate the mechanism of HSF1 degradation in neurodegenerative disease using C. elegans models. We have found that knockdown of the C. elegans homologs for FBXW7 and NEDD4, sel-10 and Y92H12A.2, does not alter HSP reporter, hsp-16.2p::GFP and hsp-70p::GFP, activity in the wildtype background. However, we also examined E3 ligase knockdown in a Huntington’s disease model that expresses polyglutamine expansions with age. In this neurodegenerative disease background, we found that sel-10 and Y92H12A.2 RNAi increased motility and thermotolerance. Thus, both E3 ligases only regulate the HSR in the presence of polyglutamine expansions. These studies provide more knowledge on the regulation of HSF-1 in neurodegenerative disease, specifically Huntington’s disease, and a potential mechanism for the decrease in HSR activity in the presence of proteotoxic aggregate formation.