Human Metapneumovirus Glycoprotein G Disrupts Mitochondrial Signaling in Airway Epithelial Cells

Xiaoyong Bao, Deepthi Kolli, Junping Ren, Tianshuang Liu, Roberto Garofalo, Antonella Casola

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Human metapneumovirus (hMPV) is a recently identified RNA virus belonging to the Paramyxoviridae family. It is a common cause of respiratory tract infections in children, adults, and immunocompromised patients, for which no specific treatment or vaccine is available. Recent investigations in our lab identified hMPV glycoprotein G as an important virulence factor, as a recombinant virus lacking the G protein (rhMPV-ΔG) exhibited enhanced production of important immune and antiviral mediators, such as cytokines, chemokines and type I interferon (IFN) in airway epithelial cells, and expression of G protein alone inhibits cellular signaling dependent on retinoic induced gene (RIG)-I, a RNA helicase with a fundamental role in initiating hMPV-induced cellular responses. In this study, we have further investigated the mechanism underlying the inhibitory role of hMPV G protein on RIG-I-dependent signaling. We found that the interaction of hMPV G with RIG-I occurs primarily through the CARD domains of RIG-I N-terminus, preventing RIG-I association with the adaptor protein MAVS (mitochondrial antiviral signaling protein), recruitment of RIG-I to mitochondria, as well as the interaction between mitochondria and mitochondria-associated membrane (MAM) component of the endoplasmic reticulum (ER), which contains STINGS, an important part of the viral-induced RIG-I/MAVS signaling pathway, leading in the end to the inhibition of cytokine, chemokine and type I IFN expression. Mutagenesis analysis showed that hMPV G protein cytoplasmic domain played a major role in the observed inhibitory activity, and recombinant viruses expressing a G protein with amino acid substitution in position 2 and 3 recapitulated most of the phenotype observed with rhMPV-ΔG mutant upon infection of airway epithelial cells.

Original languageEnglish (US)
Article numbere62568
JournalPLoS One
Volume8
Issue number4
DOIs
StatePublished - Apr 23 2013

Fingerprint

Human metapneumovirus
Metapneumovirus
glycoproteins
GTP-Binding Proteins
epithelial cells
Genes
Epithelial Cells
G-proteins
Mitochondria
Antiviral Agents
Viruses
Interferon Type I
genes
mitochondria
Chemokines
interferons
chemokines
Paramyxoviridae
RNA Helicases
Cytokines

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Human Metapneumovirus Glycoprotein G Disrupts Mitochondrial Signaling in Airway Epithelial Cells. / Bao, Xiaoyong; Kolli, Deepthi; Ren, Junping; Liu, Tianshuang; Garofalo, Roberto; Casola, Antonella.

In: PLoS One, Vol. 8, No. 4, e62568, 23.04.2013.

Research output: Contribution to journalArticle

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