title: Transcription Factor ATF4 Induces NLRP1 Inflammasome Expression during Endoplasmic Reticulum Stress.
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.
authors.affiliation: Cell Death and Survival Networks Program, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: D'Osualdo
authors.affiliation: Department of Protein Chemistry, Genentech Inc, South San Francisco, California, United States of America.
authors.forename: Veronica G
authors.initials: VG
authors.lastname: Anania
authors.affiliation: Department of Protein Chemistry, Genentech Inc, South San Francisco, California, United States of America.
authors.forename: Kebing
authors.initials: K
authors.lastname: Yu
authors.affiliation: Department of Protein Chemistry, Genentech Inc, South San Francisco, California, United States of America.
authors.forename: Jennie R
authors.initials: JR
authors.lastname: Lill
authors.affiliation: Degenerative Diseases Research Program, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.affiliation: Cell Death and Survival Networks Program, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Matsuzawa
authors.affiliation: Cell Death and Survival Networks Program, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America; Pharma Research and Early Development (pRED), Roche, Basel, Switzerland.
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D051701:Activating Transcription Factor 4 / Q000737:chemistry / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D064113:CRISPR-Cas Systems / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D019169:Jurkat Cells; D020014:K562 Cells; D016296:Mutagenesis; D000070576:NLR Proteins; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012326:RNA Splicing; D060888:Real-Time Polymerase Chain Reaction; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051701:Activating Transcription Factor 4; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D004722:Endoribonucleases; D058847:Inflammasomes; D000070576:NLR Proteins; D017346:Protein Serine-Threonine Kinases; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C427903:NLRP1 protein, human; C000605543:XBP1 protein, human; C528229:ERN1 protein, human