RIP3 Regulates Autophagy and Promotes Coxsackievirus B3 Infection of Intestinal Epithelial Cells.
Receptor 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 3C(pro), 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.
Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Katharine G
KG
Harris
Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Stefanie A
SA
Morosky
Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Coyne G
CG
Drummond
Department of Biological Sciences, Vanderbilt University, Nashville, TN 37240, USA.
Maulik
M
Patel
Virus Research and Testing Group, Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea.
Chonsaeng
C
Kim
Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Donna B
DB
Stolz
Department of Pediatrics, Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Jeffrey M
JM
Bergelson
Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Sara
S
Cherry
Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219, USA. Electronic address: coynec2@pitt.edu.
Carolyn B
CB
Coyne
D000086042:3C Viral Proteases; D001343:Autophagy; D018938:Caco-2 Cells; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D029822:Enterovirus B, Human / Q000378:metabolism / Q000502:physiology*; D004847:Epithelial Cells / Q000821:virology*; D020868:Gene Silencing; D005820:Genetic Testing; D054884:Host-Pathogen Interactions; D006801:Humans; D034622:RNA Interference; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*; D014779:Virus Replication
D014764:Viral Proteins; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases