The cargo receptor ERGIC-53 is a target of the unfolded protein response

The accumulation of unfolded proteins in the ER triggers a signaling response known as unfolded protein response (UPR). In yeast the UPR affects several hundred genes that encode ER chaperones and proteins operating at later stages of secretion. In mammalian cells the UPR appears to be more limited to chaperones of the ER and genes assumed to be important after cell recovery from ER stress that are not important for secretion. Here, we report that the mRNA of lectin ERGIC-53, a cargo receptor for the transport of glycoproteins from ER to ERGIC, and of its related protein VIP36 is induced by the known inducers of ER stress, tunicamycin and thapsigargin. In parallel, the rate of synthesis of the ERGIC-53 protein was induced by these agents. The response was due to the UPR since it was also triggered by castanospermine, a specific inducer of UPR, and inhibited by genistein. Thapsigargin-induced upregulation of ERGIC-53 could be fully accounted for by the ATF6 pathway of UPR. The results suggest that in mammalian cells the UPR also affects traffic from and beyond the ER.