RESUMEN
Virally encoded microRNAs (miRNAs) have recently been discovered in herpesviruses. However, their biological roles are mostly unknown. We developed an algorithm for the prediction of miRNA targets and applied it to human cytomegalovirus miRNAs, resulting in the identification of the major histocompatibility complex class I-related chain B (MICB) gene as a top candidate target of hcmv-miR-UL112. MICB is a stress-induced ligand of the natural killer (NK) cell activating receptor NKG2D and is critical for the NK cell killing of virus-infected cells and tumor cells. We show that hcmv-miR-UL112 specifically down-regulates MICB expression during viral infection, leading to decreased binding of NKG2D and reduced killing by NK cells. Our results reveal a miRNA-based immunoevasion mechanism that appears to be exploited by human cytomegalovirus.
Asunto(s)
Citomegalovirus/inmunología , Citomegalovirus/patogenicidad , Antígenos de Histocompatibilidad Clase I/genética , MicroARNs/metabolismo , ARN Viral/metabolismo , Regiones no Traducidas 3'/metabolismo , Algoritmos , Sitios de Unión , Línea Celular Tumoral , Células Cultivadas , Citomegalovirus/genética , Citotoxicidad Inmunológica , Regulación hacia Abajo , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Células Asesinas Naturales/inmunología , Ligandos , MicroARNs/genética , Subfamilia K de Receptores Similares a Lectina de Células NK , Receptores Inmunológicos/metabolismo , Receptores de Células Asesinas Naturales , Transducción GenéticaRESUMEN
Human cytomegalovirus, a chief pathogen in immunocompromised people, can persist in a healthy immunocompetent host throughout life without being eliminated by the immune system. Here we show that pp65, the main tegument protein of human cytomegalovirus, inhibited natural killer cell cytotoxicity by an interaction with the activating receptor NKp30. This interaction was direct and specific, leading to dissociation of the linked CD3zeta from NKp30 and, consequently, to reduced killing. Thus, pp65 is a ligand for the NKp30 receptor and demonstrates a unique mechanism by which an intracellular viral protein causes general suppression of natural killer cell cytotoxicity by specific interaction with an activating receptor.