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Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis

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Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Solis, Eric John. 2016. Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493256 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Defining the essential function of yeast Hsf1 reveals a compact transcriptional program for maintaining eukaryotic proteostasis A dissertation presented by Eric John Solis to The Committee on Higher Degrees in Systems Biology in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Systems Biology Harvard University Cambridge, Massachusetts February 2016 © 2016 Eric John Solis All rights reserved. Dissertation Advisors: Vladimir Denic and Edoardo Airoldi Eric John Solis Defining the essential function of yeast Hsf1 reveals a compact transcriptional program for maintaining eukaryotic proteostasis Abstract Despite its eponymous association with proteotoxic stress, heat shock factor 1 (Hsf1 in yeast and HSF1 in mammals) is required for viability of yeast and many human cancer cells, yet its essential role remains undefined. Here we show that rapid nuclear export of Hsf1 achieved in a matter of minutes by a chemical genetics approach results in cell growth arrest in a matter of hours, which was associated with massive protein aggregation and eventual cell death. Genome-wide analyses of immediate gene expression changes induced by Hsf1 nuclear export revealed a basal transcriptional program comprising 18 genes, predominately encoding chaperones and other proteostasis factors. During heat shock, Hsf1 increases the magnitude of its transcriptional program without expanding its breadth. Strikingly, engineered Hsf1- independent co-expression of just Hsp70 and Hsp90 chaperones enabled robust cell growth in the complete absence of Hsf1. A comparative genomic analysis of mammalian fibroblasts and embryonic stem cells revealed that HSF1 lacks a basal transcriptional program but still regulates a similar set of chaperone genes during heat shock. Our work demonstrates that basal chaperone gene expression is a housekeeping mechanism controlled by Hsf1 in yeast and serves as a roadmap for defining the housekeeping iii Dissertation Advisors: Vladimir Denic and Edoardo Airoldi Eric John Solis function of HSF1 in many cancers. Finally, we investigate the mechanism causing age- associated inactivation of Hsf1 during replicative aging in budding yeast. Using classic and chemical-genetic tools, we demonstrate that inactivation is due to constitutive activation of the distinct General Stress Response. These experiments reveal that stress pathway crosstalk inhibits Hsf1 activation during replicative aging and under physiological stress in young cells. iv Table of Contents Defining the essential function of yeast Hsf1 reveals a compact transcriptional program for maintaining eukaryotic proteostasis ............................................................................... iii! Table of Contents ................................................................................................................. v! List of figures and tables ..................................................................................................... vi! Acknowledgments .............................................................................................................. viii! Chapter 1: Introduction to proteostasis and the conserved Heat shock transcription factor. .............................................................................................................................................. 1! References ................................................................................................................................... 14! Chapter 2: Defining the essential function of yeast Hsf1 reveals a compact transcriptional program for maintaining eukaryotic proteostasis ............................................................... 25! Introduction .................................................................................................................................. 25! Results ......................................................................................................................................... 28! Discussion .................................................................................................................................... 50! Extended Discussion ................................................................................................................... 55! Experimental Procedures ............................................................................................................ 58! References ................................................................................................................................... 79! Chapter 3: Stress pathway cross-talk mediates attenuation of Hsf1 activity during stress and replicative aging in yeast. ............................................................................................ 90! Introduction .................................................................................................................................. 90! Discussion .................................................................................................................................. 132! References ................................................................................................................................. 137! Chapter 4: Future directions ............................................................................................ 144! References ................................................................................................................................. 151! Appendix: Supplementary figures and tables for Chapter 2 ............................................ 154! v List of figures and tables Figure 2.1: Acute inactivation of Hsf1 induces proteotoxicity even in the absence of stress. ......................................................................................................................... 30! Figure 2.2: Hsf1 drives basal expression of a diverse set of protein folding factors. ........ 34! Figure 2.2: (Continued) ...................................................................................................... 35! Figure 2.3: Induction of most genes by heat shock is Hsf1-independent and Msn2/4- dependent. .................................................................................................................. 39! Figure 2.3: (Continued) ...................................................................................................... 40! Figure 2.4: Mammalian HSF1 enables heat induction of a chaperone network similar to the yeast HDG network. ............................................................................................. 44! Figure 2.4: (Continued) ...................................................................................................... 45! Figure 2.5: A synthetic transcriptional program reveals the essential function of Hsf1. .... 48! Figure 3.1: Constitutive activity of the Msn2/4-mediated general stress response is necessary for age-associated attenuation of Hsf1. .................................................... 97! Figure 3.1: (Continued) ...................................................................................................... 98! Figure 3.2: Engineered activation of the general stress response inhibits Hsf1 induction by thermal and AZC stress. ........................................................................................... 100! Figure 3.2: (Continued) .................................................................................................... 101! Figure 3.3: Attenuation of Hsf1 activity following heat shock is hastened by induction of the GSR. ................................................................................................................... 106! Figure 3.3: (Continued) .................................................................................................... 107! Figure 3.3: (Continued) .................................................................................................... 108! Figure 3.4: Expression of Msn2/4 target genes antagonizes up-regulation of Hsf1 target genes during heat shock. ......................................................................................... 113! Figure 3.4: (Continued) .................................................................................................... 114! Figure 3.5: Diminished Hsf1 activity is associated with Msn2/4-dependent hyper- phosphorylation under conditions with low Pka activity. .......................................... 117! Figure 3.5: (Continued) .................................................................................................... 118! Figure 3.6: Inactivation of Hsf1 by the GSR is phosphorylation-independent and
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