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
Highlights
The endoplasmic reticulum (ER) is a specialized organelle that controls the biogenesis of membrane-anchored and secreted proteins[1]
We found that both PKR-like ER-resident kinase (PERK) and IRE1α stimulate NLRP1 gene transcription through the transcription factor ATF4, involving a mechanism that is independent of XBP-1 mRNA splicing
We showed that both the IRE1α and PERK pathways are important for ER stress-induced NLRP1 gene expression
Summary
The endoplasmic reticulum (ER) is a specialized organelle that controls the biogenesis of membrane-anchored and secreted proteins[1]. Beyond this biosynthetic role, the ER is a dynamic cellular compartment that plays critical roles in calcium storage[2] and cellular homeostasis[3]. ER imbalance activates a transcriptional and translational program known as the unfolded protein response (UPR), an adaptive signaling cascade that primarily acts to restore ER homeostasis[6]. The UPR activates three main signaling pathways initiated by different ER transmembrane sensors: PERK, IRE1α and ATF6, which cause initial shutdown in mRNA translation along with up-regulation of genes encoding.
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