3r66

Structural highlights

Function

[NS1_INBLE] Binds and inhibits the ubiquitin-like protein G1P2/ISG15, which is an early antiviral protein. Inhibits IRF-3 nuclear translocation and activation. Inhibits IFN-beta promoter activation; this inhibition is not dsRNA-binding dependent Prevents EIF2AK2/PKR activation, either by binding double strand RNA or by interacting directly with EIF2AK2/PKR. Also binds poly(A) and U6 snRNA. Suppresses the RNA silencing-based antiviral response in Drosophila cells.^[1] [ISG15_HUMAN] Ubiquitin-like protein that is conjugated to intracellular target proteins after IFN-alpha or IFN-beta stimulation. Its enzymatic pathway is partially distinct from that of ubiquitin, differing in substrate specificity and interaction with ligating enzymes. ISG15 conjugation pathway uses a dedicated E1 enzyme, but seems to converge with the Ub conjugation pathway at the level of a specific E2 enzyme. Targets include STAT1, SERPINA3G/SPI2A, JAK1, MAPK3/ERK1, PLCG1, EIF2AK2/PKR, MX1/MxA, and RIG-1. Deconjugated by USP18/UBP43. Shows specific chemotactic activity towards neutrophils and activates them to induce release of eosinophil chemotactic factors. May serve as a trans-acting binding factor directing the association of ligated target proteins to intermediate filaments. May also be involved in autocrine, paracrine and endocrine mechanisms, as in cell-to-cell signaling, possibly partly by inducing IFN-gamma secretion by monocytes and macrophages. Seems to display antiviral activity during viral infections.^{[2] [3] [4] [5] [6] [7]} In response to IFN-tau secreted by the conceptus, may ligate to and regulate proteins involved in the release of prostaglandin F2-alpha (PGF), and thus prevent lysis of the corpus luteum and maintain the pregnancy (By similarity).^{[8] [9] [10] [11] [12] [13]}

References

1. ↑ Donelan NR, Dauber B, Wang X, Basler CF, Wolff T, Garcia-Sastre A. The N- and C-terminal domains of the NS1 protein of influenza B virus can independently inhibit IRF-3 and beta interferon promoter activation. J Virol. 2004 Nov;78(21):11574-82. PMID:15479798 doi:78/21/11574
2. ↑ Loeb KR, Haas AL. The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins. J Biol Chem. 1992 Apr 15;267(11):7806-13. PMID:1373138
3. ↑ Loeb KR, Haas AL. Conjugates of ubiquitin cross-reactive protein distribute in a cytoskeletal pattern. Mol Cell Biol. 1994 Dec;14(12):8408-19. PMID:7526157
4. ↑ Narasimhan J, Potter JL, Haas AL. Conjugation of the 15-kDa interferon-induced ubiquitin homolog is distinct from that of ubiquitin. J Biol Chem. 1996 Jan 5;271(1):324-30. PMID:8550581
5. ↑ Knight E Jr, Cordova B. IFN-induced 15-kDa protein is released from human lymphocytes and monocytes. J Immunol. 1991 Apr 1;146(7):2280-4. PMID:2005397
6. ↑ Lenschow DJ, Giannakopoulos NV, Gunn LJ, Johnston C, O'Guin AK, Schmidt RE, Levine B, Virgin HW 4th. Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo. J Virol. 2005 Nov;79(22):13974-83. PMID:16254333 doi:79/22/13974
7. ↑ Zhao C, Denison C, Huibregtse JM, Gygi S, Krug RM. Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10200-5. Epub 2005 Jul 11. PMID:16009940 doi:0504754102
8. ↑ Loeb KR, Haas AL. The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins. J Biol Chem. 1992 Apr 15;267(11):7806-13. PMID:1373138
9. ↑ Loeb KR, Haas AL. Conjugates of ubiquitin cross-reactive protein distribute in a cytoskeletal pattern. Mol Cell Biol. 1994 Dec;14(12):8408-19. PMID:7526157
10. ↑ Narasimhan J, Potter JL, Haas AL. Conjugation of the 15-kDa interferon-induced ubiquitin homolog is distinct from that of ubiquitin. J Biol Chem. 1996 Jan 5;271(1):324-30. PMID:8550581
11. ↑ Knight E Jr, Cordova B. IFN-induced 15-kDa protein is released from human lymphocytes and monocytes. J Immunol. 1991 Apr 1;146(7):2280-4. PMID:2005397
12. ↑ Lenschow DJ, Giannakopoulos NV, Gunn LJ, Johnston C, O'Guin AK, Schmidt RE, Levine B, Virgin HW 4th. Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo. J Virol. 2005 Nov;79(22):13974-83. PMID:16254333 doi:79/22/13974
13. ↑ Zhao C, Denison C, Huibregtse JM, Gygi S, Krug RM. Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10200-5. Epub 2005 Jul 11. PMID:16009940 doi:0504754102