title: Kaposi's sarcoma-associated herpesviral IL-6 and human IL-6 open reading frames contain miRNA binding sites and are subject to cellular miRNA regulation.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a viral interleukin 6 (vIL-6) that mimics many activities of human IL-6 (hIL-6). Both vIL-6 and hIL-6 play important roles in stimulating the proliferation of tumours caused by KSHV. Here, we provide evidence that a miRNA pathway is involved in regulation of vIL-6 and hIL-6 expression through binding sites in their open reading frames (ORFs). We show a direct repression of vIL-6 by hsa-miR-1293 and hIL-6 by hsa-miR-608. The repression of vIL-6 by miR-1293 was reversed by disruption of the vIL-6 miR-1293 seed match through the introduction of point mutations. In addition, expression of vIL-6 or hIL-6 in KSHV-infected cells could be enhanced by transfection of the respective miRNA inhibitors. In situ hybridization of human lymph node sections revealed that miR-1293 is primarily expressed in the germinal centre but is deficient in the mantle zone of lymph nodes, where the expression of vIL-6 is often found in patients with KSHV-associated multicentric Castleman's disease, providing evidence of an anatomical correlation. Taking these factors together, our study indicates that IL-6 expression can be regulated by miRNA interactions in its ORF and provides evidence for the role of these interactions in the pathogenesis of KSHV-associated diseases.
authors: HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors: Jeong-Gu
authors: JG
authors: Kang
authors: Vladimir
authors: V
authors: Majerciak
authors: Thomas S
authors: TS
authors: Uldrick
authors: Xiaohong
authors: X
authors: Wang
authors: Michael
authors: M
authors: Kruhlak
authors: Robert
authors: R
authors: Yarchoan
authors: Zhi-Ming
authors: ZM
authors: Zheng
mesh_terms: D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017124:Conserved Sequence; D005786:Gene Expression Regulation / Q000235:genetics*; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D018858:Germinal Center / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006566:Herpesviridae Infections / Q000235:genetics / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008198:Lymph Nodes / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics; D008969:Molecular Sequence Data; D016366:Open Reading Frames / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D015850:Interleukin-6; D035683:MicroRNAs; D012367:RNA, Viral; D014764:Viral Proteins