A common critical cellular event that many human enveloped viruses share is the requirement for proteolytic cleavage of the viral
glycoprotein by
furin in the host secretory pathway. For example, the
furin-dependent proteolytic activation of highly pathogenic (HP)
influenza A (infA) H5 and H7 haemagglutinin precursor (HA0) subtypes is critical for yielding fusion-competent infectious virions. In this study, we hypothesized that viral hijacking of the
furin pathway by HP infA viruses to permit cleavage of HA0 could represent a novel molecular mechanism controlling the dynamic production of fusion-competent infectious virus particles during the viral life cycle. We explored the
biological role of a newly identified
furin-directed human
microRNA, miR-24, in this process as a potential post-transcriptional regulator of the
furin-mediated activation of HA0 and production of fusion-competent virions in the host secretory pathway. We report that miR-24 and
furin are differentially expressed in human A549 cells infected with HP avian-origin infA H5N1. Using miR-24 mimics, we demonstrated a robust decrease in both
furin mRNA levels and intracellular
furin activity in A549 cells. Importantly, pretreatment of A549 cells with miR-24 mimicked these results: a robust decrease of H5N1 infectious virions and a complete block of H5N1 virus spread that was not observed in A549 cells infected with low-pathogenicity swine-origin infA H1N1 virus. Our results suggest that viral-specific downregulation of
furin-directed
microRNAs such as miR-24 during the life cycle of HP infA viruses may represent a novel regulatory mechanism that governs
furin-mediated proteolytic activation of HA0
glycoproteins and production of infectious virions.