title: Human metapneumovirus glycoprotein G disrupts mitochondrial signaling in airway epithelial cells.
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.
authors.affiliation: Department of Pediatrics, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America. xibao@utmb.edu
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Bao
authors.forename: Deepthi
authors.initials: D
authors.lastname: Kolli
authors.forename: Junping
authors.initials: J
authors.lastname: Ren
authors.forename: Tianshuang
authors.initials: T
authors.lastname: Liu
authors.forename: Roberto P
authors.initials: RP
authors.lastname: Garofalo
authors.forename: Antonella
authors.initials: A
authors.lastname: Casola
mesh_terms: D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D029121:Metapneumovirus / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000821:virology; D015398:Signal Transduction; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C484233:G glycoprotein, human metapneumovirus; D006023:Glycoproteins; C437968:PLAAT4 protein, human; D018168:Receptors, Retinoic Acid; D014764:Viral Proteins