Regulation of the heat shock response is built into the spatial organization of the proteostasis network

How heat shock induces the heat shock response (HSR) - a gene expression program encoding chaperones and other protein homeostasis (proteostasis) factors - remains an unresolved question in eukaryotic cell biology. Here we show that subcellular localization of the conserved J-protein Sis1 is a key regulator of the HSR in yeast. Under nonstress conditions, nucleoplasmic Sis1 promotes interaction between the chaperone Hsp70 and the transcription factor Hsf1 to repress the HSR. Heat shock triggers Sis1 to localize to the periphery of the nucleolus and to condense on the ER surface. Sis1 recruits the proteasome to this spatial network along with disaggregases and the ribosome quality control complex. Through localization dynamics, Sis1 relays the condition of the proteome to Hsf1. We conclude that the activation state of the HSR is determined by the spatial organization of the proteostasis network. Overall design: We performed 12 RNA seq of polyA+ mRNA from yeast cells over two time courses: following heat shock at 39C and following nuclear depletion of the J-protein Sis1 using the "anchor away" approach. For both time series, the time points were 0, 15, 30, 60, 90 and 120 minutes.