SARAF represses the mild hypothermia response through the regulation of JUN

The mild hypothermia response (MHR) is a protective program found in mammals that is activated when exposed to temperatures around 32 degrees Celsius. This response helps to safeguard neurons during hypoxic injury and contributes to the therapeutic benefits of hypothermia therapy. While fluctuations in intracellular calcium levels occur when the body is cooled, the precise connection between calcium changes and the activation of essential MHR elements, such as SP1 and RBM3, is still being investigated.

To uncover these connections, researchers employed a technique called siRNA-mediated knockdown (KD) alongside newly developed mild hypothermia indicator (MHI) reporters. This approach allowed them to pinpoint factors that modulate MHR-associated transcription.

One such factor identified in this study was SARAF, which functions as a negative regulator of store-operated calcium entry (SOCE). SARAF was found to suppress both SP1 and RBM3 under normal body temperature conditions. When SARAF levels were reduced, it led to an increase in intracellular calcium release and a boost in the transcriptional activities controlled by SP1 and RBM3.

The researchers also discovered that JUN plays a crucial role as a downstream factor, mediating the de-repression of the MHR triggered by SARAF depletion. Upon exposure to cold temperatures, JUN activates swiftly.

The findings of this research demonstrate that SARAF acts as an upstream regulator of transcription associated with the MHR. Furthermore, it establishes a functional link between the intracellular calcium changes induced by cooling and the activation of core MHR effectors. These results provide valuable insights into the molecular mechanisms underlying the neuroprotective effects of therapeutic hypothermia following hypoxic injury.