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Cell Host Microbe. 2015 Aug 12;18(2):221-32. doi: 10.1016/j.chom.2015.07.007.

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

Author information

1
Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219, USA.
2
Department of Biological Sciences, Vanderbilt University, Nashville, TN 37240, USA.
3
Virus Research and Testing Group, Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea.
4
Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15219, USA.
5
Department of Pediatrics, Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
6
Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
7
Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219, USA. Electronic address: coynec2@pitt.edu.

Abstract

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.

PMID:
26269957
PMCID:
PMC4562276
DOI:
10.1016/j.chom.2015.07.007
[Indexed for MEDLINE]
Free PMC Article

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