Taurine ameliorates viral encephalitis by restoring PRKN-mediated mitophagy

Mitophagy is a selective type of autophagy that removes damaged mitochondria to maintain mitochondrial homeostasis and regulate the antiviral immune response. Despite increasing evidence that herpes simplex virus type 1 (HSV-1) infection causes mitochondrial damage, the regulatory mechanisms governing mitochondrial homeostasis and its biological implications in the context of HSV-1 infection and viral encephalitis remain unclear. In our recent work, we find that HSV-1 infection causes the accumulation of damaged mitochondria via defective mitophagy <i>in vitro</i> and in brain tissue of mice. The viral proteins ICP34.5 and US11 inhibit the EIF2S (eukaryotic translation initiation factor 2 subunit alpha)-ATF4 (activating transcription factor 4) axis to transcriptionally suppress <i>PRKN/Parkin</i> expression and subsequently impede PRKN-dependent mitophagy. Consequently, modulation of mitophagy significantly affects HSV-1 infection and NFKB/NF-κB-mediated neuroinflammation, as well as the severity of viral encephalitis in mice. Moreover, taurine, a metabolite differentially regulated by HSV-1 infection, transcriptionally promotes PRKN-mediated mitophagy, thereby limiting HSV-1 infection both <i>in vitro</i> and <i>in vivo</i>. This work reveals a protective function of mitophagy in restricting viral encephalitis and highlights the ATF4-PRKN axis as a potential therapeutic approach for the treatment of neurotropic virus-related diseases.<b>Abbreviations:</b> Aβ: amyloid β protein; AD: Alzheimer disease; ATF4: activating transcription factor 4; EIF2AK2/PKR: eukaryotic translation initiation factor 2 alpha kinase 2; EIF2S1: eukaryotic translation initiation factor 2 subunit alpha; HSE: herpes simplex encephalitis; HSV-1: herpes simplex virus type 1.