Abstract
Adaptation to endoplasmic reticulum (ER) stress depends on the activation of an integrated signal transduction pathway known as the unfolded protein response (UPR). Bax inhibitor-1 (BI-1) is an evolutionarily conserved ER-resident protein that suppresses cell death. Here we have investigated the role of BI-1 in the UPR. BI-1 expression suppressed IRE1alpha activity in fly and mouse models of ER stress. BI-1-deficient cells displayed hyperactivation of the ER stress sensor IRE1alpha, leading to increased levels of its downstream target X-box-binding protein-1 (XBP-1) and upregulation of UPR target genes. This phenotype was associated with the formation of a stable protein complex between BI-1 and IRE1alpha, decreasing its ribonuclease activity. Finally, BI-1 deficiency increased the secretory activity of primary B cells, a phenomenon regulated by XBP-1. Our results suggest a role for BI-1 in early adaptive responses against ER stress that contrasts with its known downstream function in apoptosis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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B-Lymphocytes / metabolism
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Cells, Cultured
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Drosophila melanogaster / metabolism
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Endoplasmic Reticulum / physiology*
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Endoribonucleases / genetics
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Endoribonucleases / metabolism*
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Humans
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Immunoglobulin M / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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Molecular Sequence Data
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA Splicing
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Regulatory Factor X Transcription Factors
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Sequence Homology, Amino Acid
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Transcription Factors / genetics
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Transcription Factors / metabolism
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X-Box Binding Protein 1
Substances
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Apoptosis Regulatory Proteins
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DNA-Binding Proteins
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Drosophila Proteins
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Immunoglobulin M
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Membrane Proteins
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Regulatory Factor X Transcription Factors
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TMBIM6 protein, human
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Transcription Factors
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X-Box Binding Protein 1
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XBP1 protein, human
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Xbp1 protein, Drosophila
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Xbp1 protein, mouse
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ERN1 protein, human
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Protein Serine-Threonine Kinases
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Endoribonucleases