title: Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) induces the expression of the cellular microRNA miR-146a.
abstract: MicroRNAs (miRNAs) are involved in sequence-specific cleavage, translational repression or deadenylation of specific target mRNAs resulting in post-transcriptional gene silencing. Epstein-Barr Virus (EBV) infection induces cellular non-coding (nc)RNAs e.g., the "vault" RNAs or miRNAs such as miR-21, miR-155 or miR-146a. MiR-146a is upregulated in various tumours and plays a role in innate immunity. We show that the EBV-encoded latent membrane protein 1 (LMP1) induces the expression of miR-146a via NFkappaB. LMP1 activates the miR-146a promoter but not a promoter with a mutation of the NFkappaB-response elements. Conversely, a LMP1-mutant deficient in NFkappaB-activation failed to activate the promoter. The "CAO"-LMP1 variant which has an increased potential to induce NFkappaB also showed a higher ability to activate the miR-146a promoter as compared to standard B95.8-LMP1. Northern blotting revealed high levels of miR-146a and miR-155 in the Burkitt's lymphoma cell line Jijoye which expresses LMP1 while the LMP1-deficient P3HR1 mutant derived from Jijoye expresses less miR-146a or miR-155. Likewise, EBV-latency type I Burkitt's lymphoma cells with low LMP1 levels also contain low levels of either miR-146a or miR-155 while their levels are increased in LMP1-expressing EBV-latency type III BL cells. Expression of LMP1 in P3HR1 cells upregulates miR-146a levels. Neither miR-146a nor miR-155 are detectable in BCBL-1 cells transformed by the Kaposi-Sarcoma Herpes virus (KSHV/HHV8). It is possible that the induction of miR-146a plays a role in the induction or maintenance of EBV latency by modulating innate immune responses to the virus infected host cell.
authors.affiliation: Institute of Virology, University of Saarland Medical School, Homburg, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Motsch
authors.forename: Thorsten
authors.initials: T
authors.lastname: Pfuhl
authors.forename: Jan
authors.initials: J
authors.lastname: Mrazek
authors.forename: Stephanie
authors.initials: S
authors.lastname: Barth
authors.forename: Friedrich A
authors.initials: FA
authors.lastname: Grässer
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology; D014763:Viral Matrix Proteins / Q000502:physiology*; D017735:Virus Latency / Q000235:genetics
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D014763:Viral Matrix Proteins