Hexanucleotide element of miR-29b interacts with IPO5 and mediates the protection of miR-29b against herpes simplex encephalitis in mice

While type I interferon (IFN-I) signaling through the IFNAR–JAK–STAT axis constitutes a major antiviral defense, IFNAR-independent mechanisms also play complementary roles in restricting viral replication. Herpes simplex virus type 1 (HSV-1), a widespread DNA virus capable of lifelong latency, can exploit the host nuclear transport machinery to facilitate its replication.

Here, we identify a distinct IFNAR-independent antiviral mechanism mediated by the nuclear-enriched microRNA miR-29b. We show that miR-29b, but not its closely related family member miR-29a, restricts HSV-1 replication by targeting the nuclear transport receptor Importin-5 (IPO5). Proteomic, imaging, and biochemical analyses reveal that miR-29b binds to IPO5 and disrupts IPO5-mediated nuclear import of the HSV-1 protein UL47, a key regulator of viral genome packaging.