Intracellular signaling pathways
Key to survival is that organisms adapt their behavior — or on the cellular level their molecular machineries — according to need. An example is how the endoplasmic reticulum (ER) accommodates fluctuations in the load of client proteins that fold and assemble there before being dispatched to travel further along the secretory pathway. A vast array of ER resident chaperones and folding factors assist maturation of client proteins. When the protein folding machinery is inadequate in letting clients mature, they accumulate in the ER, which causes stress and activates the unfolded protein response (UPR). Thus far, most studies on the UPR circuitry have focused on the signaling pathways themselves, while little is known about how the UPR evaluates the severity of ER-stress and success of homeostatic readjustment of the ER. These questions have great medical relevance, because a variety of disorders, ranging from cancer to diabetes, tie in with aberrant or maladaptive UPR-driven cell fate decisions.
The group has developed models for dissecting the intricacies of how the UPR evaluates and alleviates ER-stress. This unit recently determined that ER-stress sensing occurs in a ratiometric fashion: ER-stress sensors determine the ratio of levels of ER-client proteins requiring folding assistance from the key ER-resident chaperone BiP versus the levels of BiP, such that the signaling amplitude of the UPR is commensurate with the need for folding assistance. Activation of the UPR entails that UPR-specific transcription factors jointly initiate genetic programs that reinforce expression of all components that are necessary to expand the ER, including BiP. Successful ER homeostatic readjustment is achieved when BiP levels eclipse those of clients again.
Currently group researchers focus on elucidating the molecular mechanisms of how the UPR serves to evaluate the success of ER homeostatic readjustment, and how it contributes to initiating pro-apoptotic pathways when ER homeostatic readjustment fails.
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