Cloning of mammalian Ire1 reveals diversity in the ER stress responses.

Cells modify their gene expression pattern in response to stress signals emanating from the endoplasmic reticulum (ER). The well-characterized aspect of this response consists of the activation of genes that encode protein chaperones and other ER resident proteins, and is conserved between mammals and yeast. In mammalian cells, however, ER stress also activates other pathways, including the expression of the transcription factor CHOP/GADD153 and its downstream target genes. ER stress is also linked to the development of programmed cell death, a phenomenon in which CHOP plays an important role. Here we report on the cloning of a murine homolog of yeast IRE1, an essential upstream component of the ER stress-response in yeast. The mammalian Ire1 is located in the ER membrane and its over-expression in mammalian cells activates both the endogenous ER chaperone GRP78/BiP and CHOP-encoding genes. Over-expression of a dominant-negative form of Ire1 blocks the induction of GRP78/BiP and CHOP in response to the ER stress induced by tunicamycin treatment. Over-expression of murine Ire1 also leads to the development of programmed cell death in transfected cells. These results indicate that a single upstream component, Ire1, plays a role in multiple facets of the ER stress-response in mammalian cells.