title: Yeast Bax inhibitor, Bxi1p, is an ER-localized protein that links the unfolded protein response and programmed cell death in Saccharomyces cerevisiae.
abstract: Bax inhibitor-1 (BI-1) is an anti-apoptotic gene whose expression is upregulated in a wide range of human cancers. Studies in both mammalian and plant cells suggest that the BI-1 protein resides in the endoplasmic reticulum and is involved in the unfolded protein response (UPR) that is triggered by ER stress. It is thought to act via a mechanism involving altered calcium dynamics. In this paper, we provide evidence that the Saccharomyces cerevisiae protein encoded by the open reading frame, YNL305C, is a bona fide homolog for BI-1. First, we confirm that yeast cells from two different strain backgrounds lacking YNL305C, which we have renamed BXI1, are more sensitive to heat-shock induced cell death than wildtype controls even though they have indistinguishable growth rates at 30°C. They are also more susceptible both to ethanol-induced and to glucose-induced programmed cell death. Significantly, we show that Bxi1p-GFP colocalizes with the ER localized protein Sec63p-RFP. We have also discovered that Δbxi1 cells are not only more sensitive to drugs that induce ER stress, but also have a decreased unfolded protein response as measured with a UPRE-lacZ reporter. Finally, we have discovered that deleting BXI1 diminishes the calcium signaling response in response to the accumulation of unfolded proteins in the ER as measured by a calcineurin-dependent CDRE-lacZ reporter. In toto, our data suggests that the Bxi1p, like its metazoan homologs, is an ER-localized protein that links the unfolded protein response and programmed cell death.
authors.affiliation: Department of Biology, Providence College, Providence, Rhode Island, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Cebulski
authors.forename: Joshua
authors.initials: J
authors.lastname: Malouin
authors.forename: Nathan
authors.initials: N
authors.lastname: Pinches
authors.forename: Vincent
authors.initials: V
authors.lastname: Cascio
authors.forename: Nicanor
authors.initials: N
authors.lastname: Austriaco
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019703:Calcineurin / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D007763:Lac Operon / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics
chemical_list: C561411:Bxi1p protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000431:Ethanol; D019703:Calcineurin; D005947:Glucose