Antagonistic crosstalk fine-tunes sensitivities of IRE1 and PERK signaling during unfolded protein response

Abstract

When endoplasmic reticulum (ER) stress occurs, a collection of phylogenetically conserved signaling pathways, termed unfolded protein response (UPR) pathways, monitors the stress level in the ER and is activated to restore homeostasis. If stress is overwhelming, activation of these signaling pathways also leads to apoptosis. The initial response in the ER is fluxed into several parallel branches, i.e., IRE1, PERK, and ATF6 branch. How they coordinate in response to different ER stress levels remains largely unknown. Here, we constructed a dual-reporter system to simultaneously monitor and quantify the response of both the IRE1 and PERK branches. We found that the IRE1 and PERK branches were highly coordinated via mutual inhibition. Furthermore, IRE1 branch was more sensitive to ER stress than the PERK branch under low ER stress and IRE1 activity was attenuated under high ER stress. The differential sensitivity between the two branches arises from the interbranch inhibitor p58IPK, rather than the intra-branch inhibitor GADD34. Our results suggested a model where cells use the antagonistic crosstalk between parallel UPR signaling pathways to fine-tune their activities in response to different ER stress levels.