In response to increased demand on the protein-folding capacity of the ER, cells trigger the unfolded protein response (UPR) – a series of pathways that suppresses the flow of polypeptides into the ER and upregulates the expression of ER proteins such as chaperones. Recently, Joseph Brewer and colleagues showed that the UPR transcriptional activator XBP1 also increases synthesis of phosphatidylcholine (PtdCho; a key ER lipid) and expansion of the ER; now, on , they show that ATF6α, another UPR transcriptional activator, can also promote these changes. Using transmission electron microscopy, the authors demonstrate that the ER is enlarged and distended when a constitutively active form of ATF6α is expressed in cells in culture. Importantly, ATF6α-driven membrane expansion occurs even in the absence of active XBP1. They go on to show that the overexpression of active ATF6α induces PtdCho biosynthesis; notably, ATF6α modulates the activity of PtdCho biosynthetic enzymes differently than XBP1. The authors conclude that both XBP1 and ATF6α can induce ER expansion and lipid biosynthesis through methods that are at least partially distinct. Their data underscore the emerging complexity of the UPR and its related signalling pathways.
