Down-regulation of a host microRNA by a viral noncoding RNA.
Primate herpesviruses express more noncoding RNAs (ncRNAs) than any other class of mammalian viruses during either latency or the lytic phase of the viral life cycle. T cells transformed by the monkey virus Herpesvirus saimiri (HVS) express seven viral U-rich ncRNAs called HSURs. Conserved sequences in HSURs1 and 2 exhibit complementarity to three host-cell microRNAs (miRNAs). The predicted interactions of HSURs1 and 2 with these miRNAs were confirmed by coimmuno-precipitation experiments performed on extracts of marmoset T cells transformed by a wild-type or a mutant HVS lacking these two HSURs. Mutational analyses demonstrated that the binding of miR-27 to HSUR1 and that of miR-16 to HSUR2 involves base pairing. One of these miRNAs, miR-27, is dramatically lowered in abundance in HVS-transformed cells, with consequent effects on the expression of miR-27 target genes. Transient knockdown and ectopic expression of HSUR1 demonstrated that degradation of mature miR-27 occurs in a sequence-specific and binding-dependent manner but does not occur by AU-rich element (ARE)-mediated decay, which controls the intracellular level of HSUR1 itself. This viral strategy exemplifies the use of an ncRNA to control host-cell gene expression via the miRNA pathway and has potential applications both experimentally and therapeutically.
Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
D
D
Cazalla
J A
JA
Steitz
D000818:Animals; D001483:Base Sequence; D015536:Down-Regulation / Q000235:genetics*; D006567:Herpesvirus 2, Saimiriine / Q000235:genetics*; D054884:Host-Pathogen Interactions / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D022661:RNA, Untranslated / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics*
D035683:MicroRNAs; D022661:RNA, Untranslated; D012367:RNA, Viral