title: The human T-lymphotropic virus type 1 tax protein inhibits nonsense-mediated mRNA decay by interacting with INT6/EIF3E and UPF1.
abstract: In this report, we analyzed whether the degradation of mRNAs by the nonsense-mediated mRNA decay (NMD) pathway was affected in human T-lymphotropic virus type 1 (HTLV-1)-infected cells. This pathway was indeed strongly inhibited in C91PL, HUT102, and MT2 cells, and such an effect was also observed by the sole expression of the Tax protein in Jurkat and HeLa cells. In line with this activity, Tax binds INT6/EIF3E (here called INT6), which is a subunit of the translation initiation factor eukaryotic initiation factor 3 (eIF3) required for efficient NMD, as well as the NMD core factor upstream frameshift protein 1 (UPF1). It was also observed that Tax expression alters the morphology of processing bodies (P-bodies), the cytoplasmic structures which concentrate RNA degradation factors. The presence of UPF1 in these subcellular compartments was increased by Tax, whereas that of INT6 was decreased. In line with these effects, the level of the phosphorylated form of UPF1 was increased in the presence of Tax. Analysis of several mutants of the viral protein showed that the interaction with INT6 is necessary for NMD inhibition. The alteration of mRNA stability was observed to affect viral transcripts, such as that coding for the HTLV-1 basic leucine zipper factor (HBZ), and also several cellular mRNAs sensitive to the NMD pathway. Our data indicate that the effect of Tax on viral and cellular gene expression is not restricted to transcriptional control but can also involve posttranscriptional regulation.
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule, Unité Mixte de Recherche 5239, Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mocquet
authors.forename: Julia
authors.initials: J
authors.lastname: Neusiedler
authors.forename: Francesca
authors.initials: F
authors.lastname: Rende
authors.forename: David
authors.initials: D
authors.lastname: Cluet
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Robin
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Terme
authors.forename: Madeleine
authors.initials: M
authors.lastname: Duc Dodon
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wittmann
authors.forename: Christelle
authors.initials: C
authors.lastname: Morris
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Hir
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Ciminale
authors.forename: Pierre
authors.initials: P
authors.lastname: Jalinot
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D039621:Eukaryotic Initiation Factor-3 / Q000378:metabolism*; D016356:Gene Products, tax / Q000378:metabolism*; D057809:HEK293 Cells; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D020365:RNA Helicases; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D012191:Retroviridae Proteins; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D015534:Trans-Activators / Q000378:metabolism*; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D039621:Eukaryotic Initiation Factor-3; D016356:Gene Products, tax; C479751:HBZ protein, human T-cell leukemia virus type I; D012333:RNA, Messenger; D012191:Retroviridae Proteins; D015534:Trans-Activators; D014764:Viral Proteins; C514970:tax protein, Human T-lymphotrophic virus 1; D020365:RNA Helicases; C101828:UPF1 protein, human