Abstract
Cellular signaling pathways are often interconnected. They accurately and efficiently regulate essential cell functions such as protein synthesis, cell growth, and survival. The target of rapamycin (TOR) signaling pathway and the endoplasmic reticulum (ER) stress response pathway regulate similar cellular processes. However, the crosstalk between them has not been appreciated until recently and the detailed mechanisms remain unclear. Here, we show that ER stress-inducing drugs activate the TOR signaling pathway in S2R+ Drosophila cells. Activating transcription factor 6 (Atf6), a major stress-responsive ER transmembrane protein, is responsible for ER stress-induced TOR activation. Supporting the finding, we further show that knocking down of both site-1/2 proteases (S1P/S2P), Atf6 processing enzymes, are necessary to connect the two pathways.
Highlights
Intracellular signaling pathways are arranged as complex interrelated networks and determine virtually all aspects of essential cell functions including gene expression, mRNA translation, and proliferation; dysregulation of signaling networks will severely damage cell viability.The endoplasmic reticulum (ER) is a membranous network in the cytoplasm of the cell
Upon ER stress, perturbation of the ER is detected by three ER transmembrane protein sensors: inositol requiring enzyme 1 (IRE1), pancreatic ER kinase (PERK), and activating transcription factor 6 (Atf6)
Supporting this finding, we report that site-1 protease (S1P)/site-2 protease (S2P) proteases, which activate Activating transcription factor 6 (Atf6), are necessary to regulate the target of rapamycin (TOR) in response to ER stress
Summary
Intracellular signaling pathways are arranged as complex interrelated networks and determine virtually all aspects of essential cell functions including gene expression, mRNA translation, and proliferation; dysregulation of signaling networks will severely damage cell viability.The endoplasmic reticulum (ER) is a membranous network in the cytoplasm of the cell. Upon ER stress, perturbation of the ER is detected by three ER transmembrane protein sensors: inositol requiring enzyme 1 (IRE1), pancreatic ER kinase (PERK), and activating transcription factor 6 (Atf). Activated IRE1 removes an unconventional intron within X-box binding protein-1 (XBP1) mRNA in the cytoplasm [6, 7]. This splicing produces a functional XBP1, enhancing gene expression of ER-associated degradation (ERAD) proteins and ER chaperones. EIF2-GTP is depleted, thereby inhibiting formation of eIF2-tRNAiMet-mRNA tertiary complex, which results in an attenuation of general translation [10] Both IRE1 and PERK relieve ER stress by decreasing the load of protein synthesis entering the ER. Multiple knock out mouse models of the UPR pathway have demonstrated that the UPR pathway controls obesity, energy metabolism, and pancreatic beta cell survival [13,14,15,16,17]
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