title: IRE1α activation protects mice against acetaminophen-induced hepatotoxicity.
abstract: The mammalian stress sensor IRE1α plays a central role in the unfolded protein, or endoplasmic reticulum (ER), stress response by activating its downstream transcription factor XBP1 via an unconventional splicing mechanism. IRE1α can also induce the degradation of a subset of mRNAs in a process termed regulated IRE1-dependent decay (RIDD). Although diverse mRNA species can be degraded by IRE1α in vitro, the pathophysiological functions of RIDD are only beginning to be explored. Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in young adults in the United States and is primarily caused by CYP1A2-, CYP2E1-, and CYP3A4-driven conversion of APAP into hepatotoxic metabolites. We demonstrate here that genetic ablation of XBP1 results in constitutive IRE1α activation in the liver, leading to RIDD of Cyp1a2 and Cyp2e1 mRNAs, reduced JNK activation, and protection of mice from APAP-induced hepatotoxicity. A pharmacological ER stress inducer that activated IRE1α suppressed the expression of Cyp1a2 and Cyp2e1 in WT, but not IRE1α-deficient mouse liver, indicating the essential role of IRE1α in the down-regulation of these mRNAs upon ER stress. Our study reveals an unexpected function of RIDD in drug metabolism.
authors.affiliation: Deartment of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Kyu Yeon
authors.initials: KY
authors.lastname: Hur
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: So
authors.forename: Vera
authors.initials: V
authors.lastname: Ruda
authors.forename: Maria
authors.initials: M
authors.lastname: Frank-Kamenetsky
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.forename: Victor
authors.initials: V
authors.lastname: Koteliansky
authors.forename: Takao
authors.initials: T
authors.lastname: Iwawaki
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.forename: Ann-Hwee
authors.initials: AH
authors.lastname: Lee
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000818:Animals; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D004722:Endoribonucleases / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020871:RNA Stability / Q000235:genetics* / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000172:deficiency; D000071717:X-Box Binding Protein 1
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases