Decoding p38-Mediated Stress Response in Human Cells Using a Novel FRET Sensor

The p38 signaling pathway is the lesser understood of the three major MAPK signaling pathways in mammals, and its dysregulation is a factor in a multitude of immune disorders, cancers, and inflammatory diseases. p38α, the most ubiquitously expressed member of the p38 MAPK family, is activated by dual phosphorylation of a Thr-Gly-Tyr motif. This relatively simple activation mechanism somehow results in a complex and nuanced differential activation of several transcription factors appropriate to the activating stress that regulate differentiation, apoptosis, inflammatory response, etc. 

Through real time imaging of a FRET based p38 reporter in vivo and Hoechst nuclear staining, we have demonstrated that human cells respond to various stresses with unique changes to p38 activation state, localization patterns relative to the nucleus, and dynamics spanning several hours. Our aim is to decode stress response in human cells and potentially identify behaviors that would prove useful for medical research. Further experimentation with HIV-associated and SARS Cov-2-associated proteins could also provide unique insights into how these diseases affect immune response.