title: IRE1α cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2.
abstract: The endoplasmic reticulum (ER) is the primary organelle for folding and maturation of secretory and transmembrane proteins. Inability to meet protein-folding demand leads to "ER stress," and activates IRE1α, an ER transmembrane kinase-endoribonuclease (RNase). IRE1α promotes adaptation through splicing Xbp1 mRNA or apoptosis through incompletely understood mechanisms. Here, we found that sustained IRE1α RNase activation caused rapid decay of select microRNAs (miRs -17, -34a, -96, and -125b) that normally repress translation of Caspase-2 mRNA, and thus sharply elevates protein levels of this initiator protease of the mitochondrial apoptotic pathway. In cell-free systems, recombinant IRE1α endonucleolytically cleaved microRNA precursors at sites distinct from DICER. Thus, IRE1α regulates translation of a proapoptotic protein through terminating microRNA biogenesis, and noncoding RNAs are part of the ER stress response.
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Upton
authors.forename: Likun
authors.initials: L
authors.lastname: Wang
authors.forename: Dan
authors.initials: D
authors.lastname: Han
authors.forename: Eric S
authors.initials: ES
authors.lastname: Wang
authors.forename: Noelle E
authors.initials: NE
authors.lastname: Huskey
authors.forename: Lionel
authors.initials: L
authors.lastname: Lim
authors.forename: Morgan
authors.initials: M
authors.lastname: Truitt
authors.forename: Michael T
authors.initials: MT
authors.lastname: McManus
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
authors.forename: Andrei
authors.initials: A
authors.lastname: Goga
authors.forename: Feroz R
authors.initials: FR
authors.lastname: Papa
authors.forename: Scott A
authors.initials: SA
authors.lastname: Oakes
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis; D020126:Brefeldin A / Q000494:pharmacology; D053143:Caspase 2 / Q000235:genetics* / Q000378:metabolism*; D002474:Cell-Free System; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D050505:Mutant Proteins; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D050505:Mutant Proteins; D012333:RNA, Messenger; D020126:Brefeldin A; C528229:ERN1 protein, human; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; C490360:CASP2 protein, human; C090208:Casp2 protein, mouse; D053143:Caspase 2; D003546:Cysteine Endopeptidases