title: Viral interference with host mRNA surveillance, the nonsense-mediated mRNA decay (NMD) pathway, through a new function of HTLV-1 Rex: implications for retroviral replication.
abstract: Nonsense-mediated mRNA decay (NMD) is an essential and conserved cellular mRNA quality control mechanism. RNA signals to express viral genes from overlapping open reading frames potentially initiate NMD, nevertheless it is not clear whether viral RNAs are sensitive to NMD or if viruses have evolved mechanisms to evade NMD. Here we demonstrate that the genomic and full-length mRNAs of Human-T-cell Leukemia Virus type-I (HTLV-1), a retrovirus responsible for Adult T-cell Leukemia (ATL), are sensitive to NMD. They exhibit accelerated turnover in NMD-activated cells, while siRNA-mediated knockdown of NMD-master-regulator, UPF1, promotes enhanced stability of them. These effects on RNA stability were recapitulated by a reporter construct encoding the HTLV-1 translational frameshift signal of gag-pol. In agreement with the RNA stability, viral protein expression from the integrated provirus was inversely correlated with cellular NMD activity. We further demonstrated that the viral RNA-binding protein, Rex, approves the stability of viral RNA by inhibiting NMD. Significantly, Rex establishes a general block to NMD, as both NMD-responsive reporter transcripts and natural host-encoded NMD substrates were stabilized in the presence of Rex. Thus, we suggest that Rex not only stabilizes viral transcripts, but also perturbs cellular mRNA metabolism and host cell homeostasis via inhibition of NMD.
authors.affiliation: Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minatoku, Tokyo, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nakano
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ando
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamagishi
authors.forename: Koichi
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Takaomi
authors.initials: T
authors.lastname: Ishida
authors.forename: Takeo
authors.initials: T
authors.lastname: Ohsugi
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: David W
authors.initials: DW
authors.lastname: Brighty
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D016370:Gene Products, rex / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D059365:Nonsense Mediated mRNA Decay; D020871:RNA Stability; D012367:RNA, Viral / Q000378:metabolism; D014764:Viral Proteins / Q000096:biosynthesis; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D016370:Gene Products, rex; D012367:RNA, Viral; D014764:Viral Proteins; D037521:Virulence Factors; C514844:rex Protein, Human T-lymphotropic virus 1