RIP3 Regulates Autophagy and Promotes Coxsackievirus B3 Infection of Intestinal Epithelial Cells

•RIP3 is required for coxsackievirus B3 infection of intestinal epithelial cells•RIP3 promotes autophagic flux in intestinal epithelial cells•The coxsackievirus B3-encoded protease 3Cpro cleaves RIP3•Cleavage of RIP3 inhibits its role in necroptosis

SummaryReceptor interacting protein kinase-3 (RIP3) is an essential kinase for necroptotic cell death signaling and has been implicated in antiviral cell death signaling upon DNA virus infection. Here, we performed high-throughput RNAi screening and identified RIP3 as a positive regulator of coxsackievirus B3 (CVB) replication in intestinal epithelial cells (IECs). RIP3 regulates autophagy, a process utilized by CVB for viral replication factory assembly, and depletion of RIP3 inhibits autophagic flux and leads to the accumulation of autophagosomes and amphisomes. Additionally, later in infection, RIP3 is cleaved by the CVB-encoded cysteine protease 3Cpro, which serves to abrogate RIP3-mediated necrotic signaling and induce a nonnecrotic form of cell death. Taken together, our results show that temporal targeting of RIP3 allows CVB to benefit from its roles in regulating autophagy while inhibiting the induction of necroptotic cell death.

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