Fig. 7

Proposed mechanisms underlying the activation of cell death pathways in murine astrocytes following HSV-1 challenge. The release of genetic material or transcription of HSV-1 genes leads to nucleic acid recognition by ZBP1 and its subsequent association with RIPK3 via their respective RHIM domains, which results in phosphorylation of MLKL and the execution of necroptosis. In addition, ZBP1 association with RIPK3 can induce apoptosis via an, as yet, unknown mechanism. Alternatively, the HSV-1 viral protein ICP6 can directly interact with RIPK1 and/or RIPK3 via each of their RHIM domains causing RIPK1 and RIPK3 to associate, thereby initiating necroptosis and apoptosis in a similar manner to that caused by ZBP1/RIPK3. Finally, viral infection elicits the production of TNF-α that can act in an autocrine/paracrine manner to initiate apoptosis in the presence of function caspase-8, or necroptosis via the association of RIPK1 with RIPK3 in the absence of functional caspase-8