Dengue Virus Impairs Mitochondrial Fusion by Cleaving Mitofusins

PLoS Pathog. 2015 Dec 30;11(12):e1005350. doi: 10.1371/journal.ppat.1005350. eCollection 2015 Dec.

Abstract

Mitochondria are highly dynamic subcellular organelles participating in many signaling pathways such as antiviral innate immunity and cell death cascades. Here we found that mitochondrial fusion was impaired in dengue virus (DENV) infected cells. Two mitofusins (MFN1 and MFN2), which mediate mitochondrial fusion and participate in the proper function of mitochondria, were cleaved by DENV protease NS2B3. By knockdown and overexpression approaches, these two MFNs showed diverse functions in DENV infection. MFN1 was required for efficient antiviral retinoic acid-inducible gene I-like receptor signaling to suppress DENV replication, while MFN2 participated in maintaining mitochondrial membrane potential (MMP) to attenuate DENV-induced cell death. Cleaving MFN1 and MFN2 by DENV protease suppressed mitochondrial fusion and deteriorated DENV-induced cytopathic effects through subverting interferon production and facilitating MMP disruption. Thus, MFNs participate in host defense against DENV infection by promoting the antiviral response and cell survival, and DENV regulates mitochondrial morphology by cleaving MFNs to manipulate the outcome of infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Dengue / metabolism*
  • Dengue Virus / metabolism*
  • Flow Cytometry
  • GTP Phosphohydrolases / metabolism*
  • Host-Parasite Interactions / immunology*
  • Humans
  • Immunoprecipitation
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Mitochondrial Dynamics / physiology*
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Proteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Virus Replication / immunology

Substances

  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • GTP Phosphohydrolases
  • MFN2 protein, human
  • Mfn1 protein, human

Grants and funding

This work was supported by grants from Ministry of Science and Technology, Taiwan (www.most.gov.tw) to CYY and MMCL (NSC 101-2321-B-039-009-MY3) and to YLLi (NSC 104-2321-B-001-018 and MOST 103-2321-B-001-070) and from Academia Sinica, Taiwan (www.sinica.edu.tw). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.