5 years ago

Hsf1 and Hsp70 constitute a two-component feedback loop that regulates the yeast heat shock response

Pincus, D. S., Gross, N., K., Krakowiak, Valerius, Zheng, A. S., D., Khalil, J., X., Patel, Anandhakumar
Models for regulation of the eukaryotic heat shock response typically invoke a negative feedback loop consisting of the transcriptional activator Hsf1 and a molecular chaperone. Previously, we identified Hsp70 as the chaperone responsible for Hsf1 repression in yeast and constructed a mathematical model based on Hsp70-mediated negative feedback. The model was based on two assumptions: dissociation of Hsp70 activates Hsf1, and transcriptional induction of Hsp70 deactivates Hsf1. Here we validated these assumptions. We severed the feedback loop by uncoupling Hsp70 expression from Hsf1 regulation and found that Hsf1 was unable to efficiently deactivate. We also mapped an Hsp70 binding site on Hsf1 to a motif known as conserved element 2 (CE2). Removal of CE2 resulted in increased basal Hsf1 activity and delayed deactivation kinetics. Finally, we uncovered an auto-regulatory segment in Hsf1 that impedes its DNA binding. These results reveal the architecture and mechanisms of the cytosolic proteostasis feedback loop.

Publisher URL: http://biorxiv.org/cgi/content/short/183137v1

DOI: 10.1101/183137

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