| Structural highlights
Function
UBA7_HUMAN E1-activating enzyme that catalyzes the covalent conjugation of the ubiquitin-like protein product of ISG15 to additional interferon stimulated proteins (ISGs) as well as other cellular proteins such as P53 in a process termed protein ISGylation (PubMed:27545325). Plays an essential role in antiviral immunity together with ISG15 by restricting the replication of many viruses including rabies virus, influenza virus, sindbis virus, rotavirus or human cytomegalovirus (PubMed:16254333, PubMed:19073728, PubMed:29056542, PubMed:29743376, PubMed:37722521). For example, ISG15 modification of influenza A protein NS1 disrupts the association of the NS1 with importin-alpha leading to NS1 nuclear import inhibition (PubMed:20133869). ISGylation of human cytomegalovirs protein UL26 regulates its stability and inhibits its activities to suppress NF-kappa-B signaling (PubMed:27564865).[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
ISG15 plays a crucial role in the innate immune response and has been well-studied due to its antiviral activity and regulation of signal transduction, apoptosis, and autophagy. ISG15 is a ubiquitin-like protein that is activated by an E1 enzyme (Uba7) and transferred to a cognate E2 enzyme (UBE2L6) to form a UBE2L6-ISG15 intermediate that functions with E3 ligases that catalyze conjugation of ISG15 to target proteins. Despite its biological importance, the molecular basis by which Uba7 catalyzes ISG15 activation and transfer to UBE2L6 is unknown as there is no available structure of Uba7. Here, we present cryo-EM structures of human Uba7 in complex with UBE2L6, ISG15 adenylate, and ISG15 thioester intermediate that are poised for catalysis of Uba7-UBE2L6-ISG15 thioester transfer. Our structures reveal a unique overall architecture of the complex compared to structures from the ubiquitin conjugation pathway, particularly with respect to the location of ISG15 thioester intermediate. Our structures also illuminate the molecular basis for Uba7 activities and for its exquisite specificity for ISG15 and UBE2L6. Altogether, our structural, biochemical, and human cell-based data provide significant insights into the functions of Uba7, UBE2L6, and ISG15 in cells.
Cryo-EM structures of Uba7 reveal the molecular basis for ISG15 activation and E1-E2 thioester transfer.,Afsar M, Liu G, Jia L, Ruben EA, Nayak D, Sayyad Z, Bury PDS, Cano KE, Nayak A, Zhao XR, Shukla A, Sung P, Wasmuth EV, Gack MU, Olsen SK Nat Commun. 2023 Aug 8;14(1):4786. doi: 10.1038/s41467-023-39780-z. PMID:37553340[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ Giannakopoulos NV, Arutyunova E, Lai C, Lenschow DJ, Haas AL, Virgin HW. ISG15 Arg151 and the ISG15-conjugating enzyme UbE1L are important for innate immune control of Sindbis virus. J Virol. 2009 Feb;83(4):1602-10. PMID:19073728 doi:10.1128/JVI.01590-08
- ↑ Zhao C, Hsiang TY, Kuo RL, Krug RM. ISG15 conjugation system targets the viral NS1 protein in influenza A virus-infected cells. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2253-8. PMID:20133869 doi:10.1073/pnas.0909144107
- ↑ Park JH, Yang SW, Park JM, Ka SH, Kim JH, Kong YY, Jeon YJ, Seol JH, Chung CH. Positive feedback regulation of p53 transactivity by DNA damage-induced ISG15 modification. Nat Commun. 2016 Aug 22;7:12513. PMID:27545325 doi:10.1038/ncomms12513
- ↑ Kim YJ, Kim ET, Kim YE, Lee MK, Kwon KM, Kim KI, Stamminger T, Ahn JH. Consecutive Inhibition of ISG15 Expression and ISGylation by Cytomegalovirus Regulators. PLoS Pathog. 2016 Aug 26;12(8):e1005850. PMID:27564865 doi:10.1371/journal.ppat.1005850
- ↑ Zhao P, Jiang T, Zhong Z, Zhao L, Yang S, Xia X. Inhibition of rabies virus replication by interferon-stimulated gene 15 and its activating enzyme UBA7. Infect Genet Evol. 2017 Dec;56:44-53. PMID:29056542 doi:10.1016/j.meegid.2017.10.016
- ↑ Lee MK, Kim YJ, Kim YE, Han TH, Milbradt J, Marschall M, Ahn JH. Transmembrane Protein pUL50 of Human Cytomegalovirus Inhibits ISGylation by Downregulating UBE1L. J Virol. 2018 Jul 17;92(15):e00462-18. PMID:29743376 doi:10.1128/JVI.00462-18
- ↑ Sarkar R, Patra U, Mukherjee A, Mitra S, Komoto S, Chawla-Sarkar M. Rotavirus circumvents the antiviral effects of protein ISGylation via proteasomal degradation of Ube1L. Cell Signal. 2023 Dec;112:110891. PMID:37722521 doi:10.1016/j.cellsig.2023.110891
- ↑ Afsar M, Liu G, Jia L, Ruben EA, Nayak D, Sayyad Z, Bury PDS, Cano KE, Nayak A, Zhao XR, Shukla A, Sung P, Wasmuth EV, Gack MU, Olsen SK. Cryo-EM structures of Uba7 reveal the molecular basis for ISG15 activation and E1-E2 thioester transfer. Nat Commun. 2023 Aug 8;14(1):4786. PMID:37553340 doi:10.1038/s41467-023-39780-z
|
