Viruses cause between 10 and 15% of human cancers and represent a major public health concern. Among such oncoviruses, Kaposi’s Sarcoma Associated Herpesvirus (KSHV) is responsible for several aggressive malignancies associated with poor survival prognosis. The research group led by Sébastien Pfeffer focuses on viral microRNAs (miRNAs). These small molecules play an important role in the long-lasting persistence of the virus within the infected cell and the associated pathologies. In an article published in the journal Nucleic Acids Research, the scientists demonstrate the discovery of a novel molecular mechanism allowing KSHV to adjust the expression levels of its miRNAs.
Nowadays, no specific treatments are available to treat KSHV-induced cancers. What is more, existing antiviral molecules remain inefficient against the latent form of the virus. At the same time, this so-called latency is the main factor for oncogenesis. During the latency, the virus largely reduces the expression of its proteins that might be detected by the immune system. On the other hand, it produces high amounts of miRNAs, which are not immunogenic. The latter act via a mechanism called RNA interference in order to repress the production of proteins involved in immune response and anticancer surveillance. They are indeed crucial for the viral survival within the cell. However, to produce sufficient levels of each of its miRNAs, the virus has developed various strategies to regulate and control their biogenesis.
In this context, the team of Sébastien Pfeffer studied in detail the progressive processing of ten KSHV miRNA, which have the peculiarity of being expressed as a cluster and thus being processed from one single primary transcript. By focusing on the first step in the miRNA biogenesis, the cleavage by a multiprotein complex called the Microprocessor, the researchers have shown that it follows a particular regulatory mechanism related to the presence of some of the miRNA precursors (pre-miR-K1 and -K3) directly on the primary transcript (regulation in cis). The identification of this phenomenon led to the elaboration of a new experimental strategy in order to inhibit the expression of the cluster as a whole in infected cells. This innovative approach consists in targeting pre-miR-K1 processing with an antisense oligonucleotide. This study sheds a new light on the biogenesis of the KSHV miRNA cluster and also paves the way for a potential therapeutical development aiming at counteracting the harmful effects of viral miRNAs.
Publication link: https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkab731/6355881
Contact: Dr. Sébastien Pfeffer, firstname.lastname@example.org