Regulation of Cardiolipin Externalization in the context of Noroviral Infection

Maham Saeed, UT SOUTHWESTERN MEDICAL CENTER

Maham Saeed, UT Southwestern Medical Center, Dallas, TX Guoxun Wang, UT Southwestern Medical Center, Dallas, TX Tiffany A. Reese, UT Southwestern Medical Center, Dallas, TX

Entry and Replication

Non-enveloped viruses such as Norovirus depends on cellular lysis and membrane rupture to exit host cell, suggesting the requirement of evolved mechanisms to induce cell death. We previously reported a molecular mechanism of Norovirus-induced cell death in which the virus mimics a host MLKL-like pore-forming domain to facilitate cell death and viral egress. Viral encoded NS3 (Nonstructural Protein 3) NTPase induces host cell death by binding to cardiolipin (hallmark phospholipid of mitochondria), resulting in mitochondrial dysfunction. A key step in the Norovirus-induced cell death mechanism is the redistribution of cardiolipin from the inner mitochondrial membrane (IMM) to the outer mitochondrial membrane (OMM). However, the initiation and regulation of cardiolipin externalization remains poorly understood. Depletion of Phospholipid Scramblase 3 (Plscr3); a host enzyme responsible for the flipping of cardiolipin from IMM to OMM, leads to decreased MNoV-induced cell death and viral spread. Plscr3 promotes infection of other small RNA viruses but not DNA viruses in cells, which makes it an important target for future research. These findings suggest that Norovirus primes host cell for death through cardiolipin externalization and Plscr3 is essential for both MNoV-induced cell death as well as viral infection.