Researchers have determined how the master transcriptional regulator of the heat shock response, known as heat shock factor 1 (HSF1), is activated and controlled. This insight could lead to treatments for cancer (where HSF1’s activity is frequently hijacked) and neurodegenerative diseases (where its decreased activity may lead to the build-up of protein aggregates).
When cells undergo heat and other environmental stresses, HSF1 activates certain genes that produce chaperones, also known as heat shock proteins (HSPs). HSPs maintain the conformation, or “fold”, of other proteins within the cell under conditions that would normally cause those proteins to lose their shape and ability to function.
While HSF1 plays an important role in normal cells, it also has significant effects in cancer and neurodegenerative diseases. Many cancer cells hijack HSF1’s activity to support their extremely high rate of protein production, to help them survive the hostile environments found in tumors, and to enable cancer to spread around the body. In neurodegenerative diseases, impaired HSF1 function may allow proteins to assume incorrect conformations and clump together into aggregates. Fine-tuning HSF1’s activity in specific cell types could lead to treatments for both cancer and neurodegenerative diseases.
Although HSF1 has long been of interest for therapeutic reasons, little is known about its activation or control. Scientists have hypothesized that HSF1 is regulated by one of two methods: by a feedback loop involving some of the heat shock proteins that HSF1 controls, or by coating the HSF1 protein with phosphate groups, which is called phosphorylation.
Researchers tackled the phosphorylation hypothesis by painstakingly mapping and eliminating the 73 phosphorylation sites on the budding yeast version of HSF1 and recording the effects. Even after the scientists simultaneously removed all of the sites, HSF1’s function was only marginally affected.
The team then turned to the feedback loop hypothesis. Using a two-step immunoprecipitation technique, the researchers determined that only one of the heat shock proteins, HSP70, interacts with HSF1. HSP70’s relationship with the HSF1 protein reflects the heat shock factor’s activity—when HSP70 binds to HSF1, HSF1 is turned off; and when HSP70 dissociates from HSF1, the regulator is turned on.
According to the lab’s work in yeast experiencing heat stress, HSP70 is the primary regulator of HSF1 that acts as an on/off switch, and HSF1’s phosphorylation acts as a positive fine-tuner to sustain the regulator’s activity for a longer period of time.
Although their model, which is described this week in the journal eLife, only accounts for one type stress in one organism, the team’s research should be more broadly applicable.
“Many things are about HSF1 are conserved from yeast to humans—it turns on the same chaperone genes and binds to the same piece of DNA in yeast and humans,” says co-author of the eLife paper. “If we find out how something is regulated or activated in one species, maybe we’ll have at least some hint of what we can do to find out how it works in a different organism.”
http://wi.mit.edu/news/archive/2016/heat-shock-regulator-controlled-onoff-switch-and-phosphorylation
Heat shock regulator controlled by on/off switch and phosphorylation
- 1,281 views
- Added
Edited
Latest News
Metabolic rewiring promotes…
By newseditor
Posted 18 Apr
A drug to prevent flu-induc…
By newseditor
Posted 18 Apr
New origin of deep brain waves
By newseditor
Posted 17 Apr
Starving cells hijack prote…
By newseditor
Posted 17 Apr
Miniature battery-free epid…
By newseditor
Posted 17 Apr
Other Top Stories
Technology may help stroke victims to recover faster!
Read more
Cryo-EM structure of malaria invasion complex
Read more
Brain anatomy to identify an individual like finger printing!
Read more
Turbulence is key for large scale platelet generation form iPSC
Read more
Neurons can transmit multiple signals simultaneously
Read more
Protocols
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Modular dual-color BiAD sen…
By newseditor
Posted 31 Mar
Publications
How does the microbiota con…
By newseditor
Posted 18 Apr
The integrated stress respo…
By newseditor
Posted 18 Apr
The immunobiology of herpes…
By newseditor
Posted 17 Apr
Circulating microbiome DNA…
By newseditor
Posted 17 Apr
Spindle oscillations in com…
By newseditor
Posted 17 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar