HSF1 activity is set by the concentration of free chaperone, not by direct detection of misfolded protein. Misfolded protein acts only by consuming chaperone. This makes the heat shock response a titration circuit with negative feedback: the product of the response, chaperone, is also the repressor of the response.
From misfolding to chaperone synthesis
- Misfolded protein accumulates and binds free Hsp70 and Hsp90.
- Free chaperone concentration falls, releasing HSF1 from its inhibitory complex.
- HSF1 trimerizes and enters the nucleus.
- Trimers bind heat shock elements in target promoters.
- HSP and proteasome component genes are transcribed and translated.
- New chaperone binds misfolded clients and rebinds HSF1, terminating the response.
The heat shock response is not the same as the unfolded protein response. The heat shock response handles cytosolic and nuclear folding load through HSF1. The ER unfolded protein response is a separate program with its own sensors, covered in a later chapter.