title: Functional motifs responsible for human metapneumovirus M2-2-mediated innate immune evasion.
abstract: Human metapneumovirus (hMPV) is a major cause of lower respiratory infection in young children. Repeated infections occur throughout life, but its immune evasion mechanisms are largely unknown. We recently found that hMPV M2-2 protein elicits immune evasion by targeting mitochondrial antiviral-signaling protein (MAVS), an antiviral signaling molecule. However, the molecular mechanisms underlying such inhibition are not known. Our mutagenesis studies revealed that PDZ-binding motifs, 29-DEMI-32 and 39-KEALSDGI-46, located in an immune inhibitory region of M2-2, are responsible for M2-2-mediated immune evasion. We also found both motifs prevent TRAF5 and TRAF6, the MAVS downstream adaptors, to be recruited to MAVS, while the motif 39-KEALSDGI-46 also blocks TRAF3 migrating to MAVS. In parallel, these TRAFs are important in activating transcription factors NF-kB and/or IRF-3 by hMPV. Our findings collectively demonstrate that M2-2 uses its PDZ motifs to launch the hMPV immune evasion through blocking the interaction of MAVS and its downstream TRAFs.
authors.affiliation: Department of Pediatrics, TongJi Hospital, TongJi Medical College, Huazhong University of Science and Technology, China; Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, United States; Department of Hepatobiliary Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, China.
authors.forename: Junfang
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Pediatrics, TongJi Hospital, TongJi Medical College, Huazhong University of Science and Technology, China.
authors.forename: Jiehua
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pediatrics, TongJi Hospital, TongJi Medical College, Huazhong University of Science and Technology, China; Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Pediatrics, TongJi Hospital, TongJi Medical College, Huazhong University of Science and Technology, China; Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Shengxuan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, United States; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Prusak
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, United States; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Wood
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, United States; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, TX, United States; The Institute of Translational Science, University of Texas Medical Branch, Galveston, TX, United States; The Institute for Human Infections & Immunity, University of Texas Medical Branch, Galveston, TX, United States. Electronic address: xibao@utmb.edu.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Bao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D020816:Amino Acid Motifs; D002460:Cell Line; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D029121:Metapneumovirus / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D018184:Paramyxoviridae Infections / Q000276:immunology* / Q000821:virology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D048029:TNF Receptor-Associated Factor 6; D014764:Viral Proteins
keywords: Innate immune response; M2-2 motif; MAVS; TRAF; hMPV