RIPK3 coordinates RHIM domain–dependent antiviral inflammatory transcription in neurons

Neurons are postmitotic, nonregenerative cells that have evolved fine-tuned immunological responses to maintain life-long cellular integrity, including resistance to common programmed cell death pathways such as necroptosis. We previously demonstrated a necroptosis-independent role for the key necroptotic kinase RIPK3 in host defense against neurotropic flavivirus infection. Here, we show that RIPK3 activation had distinct outcomes in primary cortical neurons when compared with mouse embryonic fibroblasts (MEFs) during Zika virus (ZIKV) infection or after sterile activation. We found that RIPK3 activation did not induce neuronal death but instead drove antiviral gene transcription after ZIKV infection. Although RIPK3 activation in MEFs induced cell death, ablation of downstream cell death effectors unveiled a RIPK3-dependent transcriptional program that largely overlapped with that observed in ZIKV-infected neurons. In death-resistant MEFs, RIPK3-dependent transcription relied on interactions with the RHIM domain-containing proteins RIPK1 and TRIF, similar to the requirements for the RIPK3-dependent antiviral transcriptional signature in ZIKV-infected neurons. These findings suggest that the pleotropic functions of RIPK3 are largely context dependent and that in cells that are resistant to cell death, RIPK3 acts as a mediator of inflammatory transcription.