Multiple cellular signaling pathways are interconnected to maintain homeostasis in a cell. The target of rapamycin (TOR) signaling pathway is an essential regulator of cell growth and survival; the unfolded protein response (UPR) pathway is a central mechanism to counteract endoplasmic reticulum (ER) stress instigated by the accumulation of misfolded proteins in ER. Although the two pathways regulate similar cellular processes, they have been until recently studied independently. Here, we show that the UPR pathway activates the TOR signaling pathway through activating transcription factor 6 (Atf6).
Atf6 is a transmembrane protein resides in the ER membrane. Upon ER stress, cytoplasmic domain of Atf6 is processed, is translocated to the nucleus, and activates its target genes to abate the stress. We demonstrated that knocking-down of Atf6 has decreased the TOR activity in S2R+ Drosophila cells by assessing the phosphorylation state of ribosomal protein S6 kinase (S6K), a well-characterized TOR target. Conversely, overexpression of Atf6 has increased the TOR activity. Supporting the notion, knocking-down of enzymes processing Atf6 has reduced the TOR activity. Taken together, our data demonstrate that Atf6 is a key molecule to connect the two signaling pathways.