title: The Lupus Autoantigen La Prevents Mis-channeling of tRNA Fragments into the Human MicroRNA Pathway.
abstract: The Lupus autoantigen La is an RNA-binding protein that stabilizes RNA polymerase III (Pol III) transcripts and supports RNA folding and has in addition been implicated in the mammalian microRNA (miRNA) pathway. Here, we have analyzed effects of La depletion on Argonaute (Ago)-bound small RNAs in human cells. We find that in the absence of La, distinct tRNA fragments are loaded into Ago proteins. Thus, La functions as gatekeeper ensuring correct tRNA maturation and protecting the miRNA pathway from potentially functional tRNA fragments. However, one specific isoleucin pre-tRNA produces both a functional tRNA and a miRNA even when La is present. We demonstrate that the fully complementary 5' leader and 3' trailer of the pre-tRNA-Ile form a double-stranded RNA molecule that has low affinity to La. Instead, Exportin-5 (Xpo5) recognizes it as miRNA precursor and transports it into the cytoplasm for Dicer processing and Ago loading.
authors.affiliation: Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, Regensburg 93053, Germany.
authors.forename: Daniele
authors.initials: D
authors.lastname: Hasler
authors.affiliation: Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, Regensburg 93053, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Lehmann
authors.affiliation: Laboratory for RNA Biology and Posttranscriptional Regulation, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin 13125, Germany.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Murakawa
authors.affiliation: Laboratory for Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin 13125, Germany.
authors.forename: Filippos
authors.initials: F
authors.lastname: Klironomos
authors.affiliation: Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, Regensburg 93053, Germany.
authors.forename: Leonhard
authors.initials: L
authors.lastname: Jakob
authors.affiliation: Institute of Virology, Saarland University Medical School, Homburg/Saar 66421, Germany.
authors.forename: Friedrich A
authors.initials: FA
authors.lastname: Grässer
authors.affiliation: Laboratory for Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin 13125, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rajewsky
authors.affiliation: Laboratory for RNA Biology and Posttranscriptional Regulation, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin 13125, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Landthaler
authors.affiliation: Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, Regensburg 93053, Germany. Electronic address: gunter.meister@vkl.uni-regensburg.de.
authors.forename: Gunter
authors.initials: G
authors.lastname: Meister
mesh_terms: D000072283:A549 Cells; D060565:Argonaute Proteins / Q000378:metabolism; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D034622:RNA Interference; D012320:RNA Polymerase III / Q000378:metabolism; D012322:RNA Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D012355:RNA, Transfer, Ile / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection; D000097585:SS-B Antigen
chemical_list: D060565:Argonaute Proteins; D001324:Autoantigens; D053487:DEAD-box RNA Helicases; D028884:Karyopherins; D035683:MicroRNAs; D012320:RNA Polymerase III; D012322:RNA Precursors; D012355:RNA, Transfer, Ile; D012367:RNA, Viral; D043244:Ribonuclease III; D012261:Ribonucleoproteins; D000097585:SS-B Antigen; C446511:XPO5 protein, human; C408087:DICER1 protein, human