title: Nondegradative role of Atg5-Atg12/ Atg16L1 autophagy protein complex in antiviral activity of interferon gamma.
abstract: Host resistance to viral infection requires type I (α/β) and II (γ) interferon (IFN) production. Another important defense mechanism is the degradative activity of macroautophagy (herein autophagy), mediated by the coordinated action of evolutionarily conserved autophagy proteins (Atg). We show that the Atg5-Atg12/Atg16L1 protein complex, whose prior known function is in autophagosome formation, is required for IFNγ-mediated host defense against murine norovirus (MNV) infection. Importantly, the direct antiviral activity of IFNγ against MNV in macrophages required Atg5-Atg12, Atg7, and Atg16L1, but not induction of autophagy, the degradative activity of lysosomal proteases, fusion of autophagosomes and lysosomes, or the Atg8-processing protein Atg4B. IFNγ, via Atg5-Atg12/Atg16L1, inhibited formation of the membranous cytoplasmic MNV replication complex, where Atg16L1 localized. Thus, the Atg5-Atg12/Atg16L1 complex performs a pivotal, nondegradative role in IFNγ-mediated antiviral defense, establishing that multicellular organisms have evolved to use portions of the autophagy pathway machinery in a cassette-like fashion for host defense.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Seungmin
authors.initials: S
authors.lastname: Hwang
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Maloney
authors.forename: Monique W
authors.initials: MW
authors.lastname: Bruinsma
authors.forename: Gautam
authors.initials: G
authors.lastname: Goel
authors.forename: Erning
authors.initials: E
authors.lastname: Duan
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Bimmi
authors.initials: B
authors.lastname: Shrestha
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.forename: Adish
authors.initials: A
authors.lastname: Dani
authors.forename: Stanislav V
authors.initials: SV
authors.lastname: Sosnovtsev
authors.forename: Kim Y
authors.initials: KY
authors.lastname: Green
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Otin
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.forename: Larissa B
authors.initials: LB
authors.lastname: Thackray
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
mesh_terms: D000818:Animals; D001343:Autophagy; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D017250:Caliciviridae Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D029322:Norovirus / Q000502:physiology*; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C491971:Atg12 protein, mouse; C532820:Atg16l1 protein, mouse; C495773:Atg5 protein, mouse; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D008869:Microtubule-Associated Proteins; D011506:Proteins; D007371:Interferon-gamma