Abstract
The transcription factor XBP1 has been linked to the development of highly secretory tissues such as plasma cells and Paneth cells, yet its function in granulocyte maturation has remained unknown. Here we discovered an unexpectedly selective and absolute requirement for XBP1 in eosinophil differentiation without an effect on the survival of basophils or neutrophils. Progenitors of myeloid cells and eosinophils selectively activated the endoribonuclease IRE1α and spliced Xbp1 mRNA without inducing parallel endoplasmic reticulum (ER) stress signaling pathways. Without XBP1, nascent eosinophils exhibited massive defects in the post-translational maturation of key granule proteins required for survival, and these unresolvable structural defects fed back to suppress critical aspects of the transcriptional developmental program. Hence, we present evidence that granulocyte subsets can be distinguished by their differential reliance on secretory-pathway homeostasis.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Cells, Cultured
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology*
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DNA-Binding Proteins / metabolism
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Endoplasmic Reticulum Stress / genetics
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Endoplasmic Reticulum Stress / immunology
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Endoribonucleases / genetics
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Endoribonucleases / immunology
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Endoribonucleases / metabolism
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Eosinophils / immunology*
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Eosinophils / metabolism
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Eosinophils / ultrastructure
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Flow Cytometry
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Gene Expression / immunology*
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Gene Expression Profiling
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Granulocyte Precursor Cells / immunology
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Granulocyte Precursor Cells / metabolism
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Granulocyte Precursor Cells / ultrastructure
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HEK293 Cells
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Humans
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Microscopy, Confocal
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Microscopy, Electron, Transmission
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / immunology
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Protein Serine-Threonine Kinases / metabolism
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Regulatory Factor X Transcription Factors
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics
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Signal Transduction / immunology
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Transcription Factors / genetics
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Transcription Factors / immunology*
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Transcription Factors / metabolism
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X-Box Binding Protein 1
Substances
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DNA-Binding Proteins
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Regulatory Factor X Transcription Factors
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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, mouse
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Ern1 protein, mouse
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Protein Serine-Threonine Kinases
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Endoribonucleases