HSV-1 ICP0 expression induces formation of nuclear TDP-43 assemblies

Toxic cytoplasmic aggregates containing the nuclear RNA-binding protein TDP-43 form in several neurodegenerative diseases; however, the molecular triggers driving aggregation remain unclear. Epidemiological evidence has linked latent and reactivating herpes simplex virus type-1 (HSV-1) infections to neurodegenerative disease onset, but it is unknown if HSV-1 infection impacts TDP-43 subcellular distribution. Here, we demonstrate that HSV-1 infection of epithelial cells and DRG-derived neurons results in nuclear TDP-43 redistribution and TDP-43 accumulation within distinct nuclear assemblies. Cytoplasmic TDP-43 was not detected under these conditions. Nuclear TDP-43 assembly occurred early in infection and was dependent upon expression of the critical ICP0 regulatory gene. Remarkably, ectopic ICP0 expression in uninfected cells was sufficient for nuclear TDP-43 assembly. Thus, expression of a single viral gene product encoded by a near ubiquitous human herpesvirus can alter TDP-43 nuclear localization. Moreover, our work identifies a potential mechanistic link between herpesvirus infection and neuronal disease factor mislocalization.