Abstract
Perturbation of endoplasmic reticulum (ER) homeostasis triggers the ER stress response (also known as Unfolded Protein Response), a hallmark of many pathological disorders. However the connection between ER stress and inflammation remains largely unexplored. Recent data suggest that ER stress controls the activity of inflammasomes, key signaling platforms that mediate innate immune responses. Here we report that expression of NLRP1, a core inflammasome component, is specifically up-regulated during severe ER stress conditions in human cell lines. Both IRE1α and PERK, but not the ATF6 pathway, modulate NLRP1 gene expression. Furthermore, using mutagenesis, chromatin immunoprecipitation and CRISPR-Cas9-mediated genome editing technology, we demonstrate that ATF4 transcription factor directly binds to NLRP1 promoter during ER stress. Although involved in different types of inflammatory responses, XBP-1 splicing was not required for NLRP1 induction. This study provides further evidence that links ER stress with innate.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Activating Transcription Factor 4 / chemistry
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Activating Transcription Factor 4 / metabolism*
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Apoptosis Regulatory Proteins / chemistry
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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CRISPR-Cas Systems / genetics
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Endoplasmic Reticulum / metabolism*
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Endoplasmic Reticulum Stress*
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Endoribonucleases / metabolism
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HCT116 Cells
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HeLa Cells
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Humans
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Inflammasomes / metabolism*
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Jurkat Cells
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K562 Cells
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Mutagenesis
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NLR Proteins
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Promoter Regions, Genetic
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Protein Binding
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Protein Serine-Threonine Kinases / metabolism
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RNA Splicing
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Real-Time Polymerase Chain Reaction
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Regulatory Factor X Transcription Factors
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Signal Transduction
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Up-Regulation
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X-Box Binding Protein 1
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eIF-2 Kinase / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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DNA-Binding Proteins
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Inflammasomes
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NLR Proteins
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NLRP1 protein, human
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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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Activating Transcription Factor 4
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ERN1 protein, human
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PERK kinase
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Protein Serine-Threonine Kinases
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eIF-2 Kinase
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Endoribonucleases