Elucidating the molecular mechanisms of regulation of cellular stress sensors

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Responses to stress are an integral part of organism's physiology and biology. Adaptation to stressful conditions is a decisive advantage in the evolutionary struggle for existence. The endoplasmic reticulum (ER) is a centrally located intracellular organelle responsible for many housekeeping functions including the synthesis, folding of proteins and lipids, the storage and release of intracellular calcium. Disruption of ER function caused by many intrinsic or extrinsic factors culminates in ER stress, and the ER mounts a coping response [e.g., unfolded protein response (UPR)] to mitigate or eliminate the stress. The UPR pathways sense ER disturbance and involves distinct components designed to re-establish the protein synthetic machinery, including translational attenuation, transcriptional activation of genes encoding chaperones and components of the ER-associated degradation, and activation of apoptotic and autophagy pathways. There are three ER transmembrane stress sensors that comprise the UPR reaction to ER stress: PERK, ATF6, and IRE1, integral ER proteins with luminal stress sensing domains. Our research program is focused on identifying the molecular mechanisms involved in the regulation of cellular stress sensors. Long-term objectives of this research are to generate fundamental knowledge regarding molecular mechanisms of stress sensors and to provide unique training opportunity for HQP engaged in the program. Regulation of the luminal sensor domain of UPR by the ER luminal environment remains poorly understood. This research program was initiated in 2014 to address this knowledge gap. We discovered that ER resident proteins (oxidoreductase, cyclooxygenase and calsequestrin) bind to ER luminal stress sensing domain of IRE to affect its cellular signaling. However, the molecular mechanisms governing these interactions are not known. Furthermore, regulation of other ER stress sensors remains to be examined. To address these our research program has three themes focused on reconstituting the mechanistic events in vitro, using recombinant IRE1, PERK and ATF6 luminal domain, in the presence of relevant ER resident proteins; and assessing whether ER luminal environment is involved in this process. Theme 1. Determine the nature of ER luminal stress sensors Theme 2. Examine molecular regulation of PERK and ATF6 ER stress sensors Theme 3. Determine biological importance of ER stress sensors regulation This research program will yield new insights on ER stress sensors biology, the importance of molecular interaction in stress sensing, as well as advance our general understanding of ER stress coping responses. We also provide outstanding environment for training of HQP in technologies and skills desired by industry and academic job sectors. Longer-term indicators of our success will be percentages of trainees reaching senior, influential positions as academic researchers, industry leaders or government policy makers.