Yeast Bax Inhibitor‐1 (BXI1/YBH3) encodes a protein (Bxi1p) that belongs to the Bax Inhibitor family of proteins. In mammals, this family of proteins has cytoprotective properties that are most evident in paradigms of endoplasmic reticulum (ER) stress and have been linked to several human cancers. Both the crystal structure of a prokaryotic member of the family (BsYetJ) and our own published studies suggest that yeast Bxi1p is a pH‐sensitive calcium leak channel localized to the ER membrane. It is involved in the unfolded protein response (UPR). Bxi1p is thought to act via a mechanism involving altered calcium dynamics. We now show that cells lacking BXI1 have an altered redox microenvironment in the ER. We also report that cells lacking BXI1 accumulate more calcium in the ER than wild type cells. Together, our data suggest that Bxi1p is involved in regulating the ER microenvironment and, consequently, programmed cell death.Support or Funding InformationOur laboratory is supported by grant NIGMS R15 GM110578, awarded to N. Austriaco.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

In mammals, the Bax inhibitor (TMBIM) family of proteins has cytoprotective properties that are most evident in paradigms of endoplasmic reticulum (ER) stress. The canonical gene of the family called BI-1 has been linked to several human cancers. The crystal structure of a prokaryotic member of the family, BsYetJ, has revealed that the Bax inhibitor proteins are pH sensitive calcium leaks. Our published studies have shown that the yeast Bax Inhibitor, Bxi1p, is localized to the endoplasmic reticulum and is involved in the unfolded protein response (UPR) that is triggered by endoplasmic reticulum (ER) stress. We now show that cells lacking BXI1 have an altered redox microenvironment in the ER: The ER of Δbxi1 cells exposed to dithiothreitol (DTT) and tunicamycin, two drugs known to induce the unfolded protein response (UPR), become more reduced than their wildtype counterparts. Moreover, we also report that cells lacking BXI1 accumulate more calcium in the ER than wildtype cells. Together, our data suggests that Bxi1p is involved in regulating the ER microenvironment. Other members of the TMBIM family may have the same role in normal and cancer cells. [Our laboratory is supported by grant NIGMS R15 GM110578, awarded to N. Austriaco.] Note: This abstract was not presented at the meeting. Citation Format: David Eagan, Joseph Alisch, Liam McDonough, Savannah Benko, Walter Jacob, Lukas Ritzer, James Mullin, John O'Reilly, Nicanor Austriaco. Yeast Bax Inhibitor (BXI1) is involved in redox and calcium homeostasis of the ER in S. cerevisiae [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5472. doi:10.1158/1538-7445.AM2017-5472

Yeast Bax inhibitor-1 (BXI1/YBH3) encodes a protein that belongs to the Bax Inhibitor (TMBIM) family of proteins that all contain a transmembrane BAX inhibitor motif. The crystal structure of a prokaryotic member of the family, BsYetJ, has revealed that the Bax inhibitor proteins are pH sensitive calcium leaks. In mammals, the Bax inhibitor family of proteins has cytoprotective properties that are most evident in paradigms of endoplasmic reticulum (ER) stress. Our published studies have shown that yeast Bxi1p is localized to the endoplasmic reticulum and is involved in the unfolded protein response (UPR) that is triggered by ER stress. BXI1 is thought to act via a mechanism involving altered calcium dynamics. We now show that cells lacking BXI1 accumulate higher levels of calcium in their ER as compared to their wildtype counterparts. We have also over expressed Bxi1p in E.coli and have used a fura-2 based calcium assay to show that the protein facilitates the influx of extracellular calcium into the cell. Our preliminary data with Δbxi1 Δpmr1 double mutants suggest that Bxi1p and Pmr1p, the Golgi-ER calcium pump, function in an antagonistic manner. [Our laboratory is supported by grant NIGMS R15 GM110578, awarded to N. Austriaco.] Citation Format: Nicholas Andrews, Nicholas Mello, Liam McDonough, Joseph Alisch, David Eagan, James Mullin, Alfredo Gonzalez, Nicanor Austriaco. Yeast Bax Inhibitor, BXI1, is involved in calcium homeostasis of the ER in Saccharomyces cerevisiae [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 308.