TY - JOUR
T1 - Nondegradative role of Atg5-Atg12/Atg16L1 autophagy protein complex in antiviral activity of interferon gamma
AU - Hwang, Seungmin
AU - Maloney, Nicole S.
AU - Bruinsma, Monique W.
AU - Goel, Gautam
AU - Duan, Erning
AU - Zhang, Lei
AU - Shrestha, Bimmi
AU - Diamond, Michael S.
AU - Dani, Adish
AU - Sosnovtsev, Stanislav V.
AU - Green, Kim Y.
AU - Lopez-Otin, Carlos
AU - Xavier, Ramnik J.
AU - Thackray, Larissa B.
AU - Virgin, Herbert W.
N1 - Funding Information:
This work was supported by the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (U54 AI065982), National Institutes of Health grants AI054483, CA096511, and AI084887, and the Rheumatic Diseases Core Center (NIH P30 AR48335). We thank the Genome Technology Access Center at Washington University School of Medicine for help with genomic analysis (supported by NCI Cancer Center Support Grant number P30 CA91842 and ICTS/CTSA grant number UL1RR024992). Washington University and H.W.V. receive income based on licenses for MNV technology. C.L.O. was supported by grants from Ministry of Science and Innovation-Spain, FP7 (Microenvimet), and Fundacion M. Botin. We would like to thank Masaaki Komatsu (Tokyo Metropolitan Institute of Medical Science, Japan) for Atg7 F/F mouse, Noboru Mizushima (Tokyo Medical and Dental University, Japan) for Atg5 F/F mouse, Tamotsu Yoshimori (Osaka University, Japan) for Atg4B/C74A and Rab7A/T22N constructs. We thank Virgin lab members for their comments on the manuscript and D. Kreamalmeyer and M. White for managing mouse colonies.
PY - 2012/4/19
Y1 - 2012/4/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84859982621&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2012.03.002
DO - 10.1016/j.chom.2012.03.002
M3 - Article
C2 - 22520467
AN - SCOPUS:84859982621
SN - 1931-3128
VL - 11
SP - 397
EP - 409
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 4
ER -