HSV-1-encoded microRNA miR-H1 targets Ubr1 to promote accumulation of neurodegeneration-associated protein.

Herpes simplex virus 1 (HSV-1) encodes various microRNAs (miRNAs), whose targets are largely unknown. miR-H1 is the first discovered HSV-1 miRNA and is expressed predominantly in productive infection. Here we show that ubiquitin protein ligase E3 component n-recognin 1 (Ubr1) is a cellular target of miR-H1. Ubr1 is a RING-type E3 ubiquitin ligase of the Arg/N-end rule pathway, which causes the degradation of proteins bearing "destabilizing" N-terminal residues, such as neurodegeneration-associated protein fragment β-amyloid. Using model substrates, we found that miR-H1 significantly repressed the expression and activity of Ubr1. Consequently, miR-H1-mediated Ubr1 silencing resulted in the accumulation of β-amyloid, which might contribute to the neurodegenerative pathogenesis enhanced by HSV-1. Our results provide novel insights into the mechanism by which HSV-1-encoded miR-H1 functions in neurodegenerative pathogenesis through targeting Ubr1-mediated Arg/N-end rule degradation pathway.