Induction of Sis1 promotes fitness but not feedback in the heat shock response

The heat shock response (HSR) controls expression of molecular chaperones
to maintain protein homeostasis. Previously, we proposed a
feedback loop model of the HSR in which heat-denatured proteins sequester
the chaperone Hsp70 to activate the HSR, and subsequent induction
of Hsp70 deactivates the HSR. However, recent work has implicated
newly synthesized proteins (NSPs) – rather than unfolded mature
proteins – and the Hsp70 co-chaperone Sis1 in HSR regulation, yet their
contributions to HSR dynamics have not been determined. Here we
generate a new mathematical model that incorporates NSPs and Sis1
into the HSR activation mechanism, and we perform genetic
decoupling and pulse-labeling experiments to demonstrate that
Sis1 induction is dispensable for HSR deactivation. Rather than
providing negative feedback to the HSR, transcriptional regulation of Sis1
by Hsf1 promotes fitness by coordinating stress granules and
carbon metabolism. These results support an overall model in
which NSPs signal the HSR by sequestering Sis1 and Hsp70,
while induction of Hsp70 – but not Sis1 – attenuates the
response.