| Structural highlights
Function
ICP27_HHV11 Multifunctional regulator of the expression of viral genes that contributes to the shutoff of host protein synthesis and mediates nuclear export of viral intronless mRNAs. Early in infection, this immediate early (EI) protein mediates the inhibition of cellular splicing. This results in the accumulation of unprocessed 3'end pre-mRNAs which can't be exported from the nucleus. Cellular protein synthesis is thereby shut off early after virus infection. Later in the infection, it helps recruit cellular RNA polymerase II to viral replication sites and promotes the nuclear export of viral intronless mRNAs by interacting with mRNAs and host NXF1/TAP. ICP27 binds to NUP62 which may provide facilitated viral mRNA export and may indirectly compete with some host cell transport receptors for binding and inhibit cellular nucleocytoplasmic transport pathways. Also stimulates translation of viral transcripts. Repression of host gene expression blocks the cell cycle at the G1 phase and prevents apoptosis. Seems to silence the 3' splice site of the promyelocytic leukemia (PML) intron 7a, thereby switching PML isoforms from PML-II to PML-V. This could be linked to the accelerated mRNA export induced by ICP27 which might not provide sufficient time for PML pre-mRNA to be spliced in the nucleus.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Herpes viruses are nuclear-replicating viruses that have successfully evolved to evade the immune system of humans, establishing life-long infections. ICP27 from herpes simplex virus (HSV) is a multifunctional regulatory protein that is functionally conserved in all known human herpes viruses. It has the potential to interact with an array of cellular proteins as well as intronless viral RNAs. ICP27 plays an essential role in viral transcription, nuclear export of intronless RNAs, translation of viral transcripts and virion host shut-off function. It has also been implicated in several signaling pathways and prevention of apoptosis. Although much is known about its central role in viral replication and infection, very little is known about the structure and mechanistic properties of ICP27 and its homologs. We present the first crystal structure of ICP27 C-terminal domain at 2.0 A resolution. The structure reveals the C-terminal half of ICP27 to have a novel fold consisting of alpha-helices and long loops, along with a unique CHCC-type of zinc-binding motif. The two termini of this domain extend out from the central core and hint to possibilities of making interactions. ICP27 essential domain is capable of forming self-dimers as seen in the structure, which is confirmed by analytical ultracentrifugation study. Preliminary in vitro phosphorylation assays reveal that this domain may be regulated by cellular kinases. IMPORTANCE: ICP27 is a key regulatory protein of the Herpes Simplex Virus and has functional homologs in all known human herpes viruses. Understanding the structure of this protein is a step ahead in deciphering the mechanism by which the virus thrives. In this study, we present the first structure of the C-terminal domain of ICP27 and describe its novel features. We critically analyze the structure and compare our results to the information available form earlier studies. This structure can act as a guide in future experimental designs, and can add to a better understanding of mechanism of ICP27 as well as that of its homologs.
Structure of C-Terminal Domain of the Multifunctional ICP27 Protein from Herpes Simplex Virus-1.,Patel V, Dahlroth SL, Rajakannan V, Ho HT, Cornvik T, Nordlund P J Virol. 2015 Jun 17. pii: JVI.00441-15. PMID:26085142[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bryant HE, Wadd SE, Lamond AI, Silverstein SJ, Clements JB. Herpes simplex virus IE63 (ICP27) protein interacts with spliceosome-associated protein 145 and inhibits splicing prior to the first catalytic step. J Virol. 2001 May;75(9):4376-85. PMID:11287586 doi:http://dx.doi.org/10.1128/JVI.75.9.4376-4385.2001
- ↑ Sciabica KS, Dai QJ, Sandri-Goldin RM. ICP27 interacts with SRPK1 to mediate HSV splicing inhibition by altering SR protein phosphorylation. EMBO J. 2003 Apr 1;22(7):1608-19. PMID:12660167 doi:http://dx.doi.org/10.1093/emboj/cdg166
- ↑ Dai-Ju JQ, Li L, Johnson LA, Sandri-Goldin RM. ICP27 interacts with the C-terminal domain of RNA polymerase II and facilitates its recruitment to herpes simplex virus 1 transcription sites, where it undergoes proteasomal degradation during infection. J Virol. 2006 Apr;80(7):3567-81. PMID:16537625 doi:http://dx.doi.org/10.1128/JVI.80.7.3567-3581.2006
- ↑ Johnson LA, Li L, Sandri-Goldin RM. The cellular RNA export receptor TAP/NXF1 is required for ICP27-mediated export of herpes simplex virus 1 RNA, but the TREX complex adaptor protein Aly/REF appears to be dispensable. J Virol. 2009 Jul;83(13):6335-46. doi: 10.1128/JVI.00375-09. Epub 2009 Apr 15. PMID:19369354 doi:http://dx.doi.org/10.1128/JVI.00375-09
- ↑ Souki SK, Sandri-Goldin RM. Arginine methylation of the ICP27 RGG box regulates the functional interactions of ICP27 with SRPK1 and Aly/REF during herpes simplex virus 1 infection. J Virol. 2009 Sep;83(17):8970-5. Epub 2009 Jun 24. PMID:19553338 doi:http://dx.doi.org/JVI.00801-09
- ↑ Malik P, Tabarraei A, Kehlenbach RH, Korfali N, Iwasawa R, Graham SV, Schirmer EC. Herpes simplex virus ICP27 protein directly interacts with the nuclear pore complex through Nup62, inhibiting host nucleocytoplasmic transport pathways. J Biol Chem. 2012 Apr 6;287(15):12277-92. doi: 10.1074/jbc.M111.331777. Epub 2012, Feb 14. PMID:22334672 doi:http://dx.doi.org/10.1074/jbc.M111.331777
- ↑ Sandri-Goldin RM. ICP27 mediates HSV RNA export by shuttling through a leucine-rich nuclear export signal and binding viral intronless RNAs through an RGG motif. Genes Dev. 1998 Mar 15;12(6):868-79. PMID:9512520
- ↑ Patel V, Dahlroth SL, Rajakannan V, Ho HT, Cornvik T, Nordlund P. Structure of C-Terminal Domain of the Multifunctional ICP27 Protein from Herpes Simplex Virus-1. J Virol. 2015 Jun 17. pii: JVI.00441-15. PMID:26085142 doi:http://dx.doi.org/10.1128/JVI.00441-15
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