When cells come under environmental stress, they employ a variety of molecular adjustments to survive. Stress can result in protein misfolding and aggregation, so protein synthesis is reduced and comes under tight regulation within the cell. The finely orchestrated molecular machinery involved with this adaptation remains poorly understood, however.
A research team led by JAX Assistant Professor Chengkai Dai, M.D., Ph.D., has explored the mechanisms involved with the heat-shock response, which cells employ in response to some types of stress. Heat-shock proteins, including heat shock factor 1 (HSF1, the primary regulator of the response), are protein chaperones that protect against misfolding and aggregation, thus allowing cells and organisms to survive hostile environmental conditions. On the other side of the equation, a protein called c-JUN N-terminal kinase (JNK) is involved with the suppression of protein synthesis. In a paper published in Nature Cell Biology, Dai and colleagues show the interplay between the two functions that allows for optimal growth when under stress.
JNK associates with a protein complex, mTORC1, during normal conditions. In the presence of stress, JNK disintegrates mTORC1, which in turn suppresses protein synthesis. HSF1, on the other hand, removes JNK from the mTORC1 complex and inactivates it, allowing for key proteins to be produced, allowing the cell to maintain appropriate function and growth. The findings highlight a key role for HSF1 in maintaining protein translation at an operational level appropriate for stressful conditions.
HSF1 critically attunes proteotoxic stress sensing by mTORC1 to combat stress and promote growth. 2016. doi:10.1038/ncb3335