| Structural highlights
Function
PG065_VACCW RNA-binding protein that plays a role in the inhibition of multiple cellular antiviral responses activated by double-stranded RNA (dsRNA), such as inhibition of PKR activation, necroptosis, and IFN-mediated antiviral activities (PubMed:1350676, PubMed:1681618, PubMed:18604270, PubMed:24257616, PubMed:25740987). Recognizes and binds Z-RNA structures via its Z-binding domain and dsRNA via its DRBM domain: RNA-binding activity is required to escape host ZBP1-dependent necroptosis (PubMed:29073079, PubMed:34192517). Mechanistically, the Z-binding domain binds Z-RNAs that are produced during vaccinia virus infection, thereby competing with Z-RNA detection by host ZBP1, suppressing ZBP1-dependent necroptosis (PubMed:34192517). Acts as a key inhibitor of the interferon response by blocking the phosphorylation and subsequent activation of IRF3 and IRF7 kinases that are required for interferon-alpha gene expression (PubMed:22419806). Inhibits NF-kappa-B activation and the ubiquitin-like protein ISG15, which is an early antiviral protein (PubMed:18604270, PubMed:24257616). The binding with host ISG15 subsequently blocks host ISGylation (PubMed:18604270, PubMed:24257616).[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
E3L (RNA-binding protein E3) is one of the key IFN resistance genes encoded by VV and consists of 190 amino acids with a highly conserved carboxy-terminal double-stranded RNA-binding domain (dsRBD). PKR (dsRNA-dependent protein kinase) is an IFN-induced protein involved in anti-cell and antiviral activity. PKR inhibits the initiation of translation through alpha subunit of the initiation factor eIF2 (eIF2alpha) and mediates several transcription factors such as NF-kappaB, p53 or STATs. Activated PKR also induces apoptosis in vaccinia virus infection. E3L is required for viral IFN resistance and directly binds to PKR to block activation of PKR. In this work, we determined the three-dimensional complex structure of E3L and PKR using cryo-EM and determined the important residues involved in the interaction. In addition, PKR peptide binds to E3L and can increase protein levels of phosphorus-PKR and phosphorus-eIF2alpha-induced cell apoptosis through upregulation of phosphorus-PKR in HEK293 cells. Taken together, structural insights into E3L and PKR will provide a new optimization and development of vaccinia virus drugs.
Structural study of novel vaccinia virus E3L and dsRNA-dependent protein kinase complex.,Kim HJ, Han CW, Jeong MS, Jang SB Biochem Biophys Res Commun. 2023 Jul 12;665:1-9. doi: 10.1016/j.bbrc.2023.04.107. , Epub 2023 Apr 29. PMID:37146409[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Watson JC, Chang HW, Jacobs BL. Characterization of a vaccinia virus-encoded double-stranded RNA-binding protein that may be involved in inhibition of the double-stranded RNA-dependent protein kinase. Virology. 1991 Nov;185(1):206-16. PMID:1681618 doi:10.1016/0042-6822(91)90768-7
- ↑ Guerra S, Cáceres A, Knobeloch KP, Horak I, Esteban M. Vaccinia virus E3 protein prevents the antiviral action of ISG15. PLoS Pathog. 2008 Jul 4;4(7):e1000096. PMID:18604270 doi:10.1371/journal.ppat.1000096
- ↑ White SD, Jacobs BL. The amino terminus of the vaccinia virus E3 protein is necessary to inhibit the interferon response. J Virol. 2012 May;86(10):5895-904. PMID:22419806 doi:10.1128/JVI.06889-11
- ↑ Eduardo-Correia B, Martínez-Romero C, García-Sastre A, Guerra S. ISG15 is counteracted by vaccinia virus E3 protein and controls the proinflammatory response against viral infection. J Virol. 2014 Feb;88(4):2312-8. PMID:24257616 doi:10.1128/JVI.03293-13
- ↑ Dueck KJ, Hu YS, Chen P, Deschambault Y, Lee J, Varga J, Cao J. Mutational analysis of vaccinia virus E3 protein: the biological functions do not correlate with its biochemical capacity to bind double-stranded RNA. J Virol. 2015 May;89(10):5382-94. PMID:25740987 doi:10.1128/JVI.03288-14
- ↑ Koehler H, Cotsmire S, Langland J, Kibler KV, Kalman D, Upton JW, Mocarski ES, Jacobs BL. Inhibition of DAI-dependent necroptosis by the Z-DNA binding domain of the vaccinia virus innate immune evasion protein, E3. Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11506-11511. PMID:29073079 doi:10.1073/pnas.1700999114
- ↑ Koehler H, Cotsmire S, Zhang T, Balachandran S, Upton JW, Langland J, Kalman D, Jacobs BL, Mocarski ES. Vaccinia virus E3 prevents sensing of Z-RNA to block ZBP1-dependent necroptosis. Cell Host Microbe. 2021 Aug 11;29(8):1266-1276.e5. PMID:34192517 doi:10.1016/j.chom.2021.05.009
- ↑ Kim HJ, Han CW, Jeong MS, Jang SB. Structural study of novel vaccinia virus E3L and dsRNA-dependent protein kinase complex. Biochem Biophys Res Commun. 2023 Jul 12;665:1-9. PMID:37146409 doi:10.1016/j.bbrc.2023.04.107
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