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Gene Review

US11  -  dsRNA-binding protein; antagonizes PKR;...

Human herpesvirus 1

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Disease relevance of US11

  • Herpes simplex virus-1 US11 is a RNA-binding protein with a novel RNA-binding domain [1].
  • Densitometric analysis of purified virions showed that the levels of VP11/12 and VP13/14 in the virion tegument were near the molar ratios of alpha TIF [2].
  • Thus, although required for efficient replication, the myristylated HSV-1 virion protein, in contrast to those of many other viruses, is not essential for virus growth in tissue culture [3].
  • L-particles are noninfectious virion-related particles that lack the nucleocapsid but do contain tegument and envelope [4].
  • An oligonucleotide consisting of 19 nucleotides spanning the TATA box of the HSV-1 true late US11 gene drove barely detectable levels of expression; by contrast, the corresponding regions of the Adenovirus type 2 major late promoter and the HSV-1 true late glycoprotein C promoter were much more active [5].

High impact information on US11

  • The infectious virion is an enveloped capsid containing the viral polymerase and double-stranded DNA genome [6].
  • We propose that when the intrinsic capacity of neurons to inhibit HSV-1 reactivation from latency is compromised, production of HSV-1 immediate early and early proteins might activate CD8(+) T cells aborting virion production [7].
  • The herpes simplex virus 1 ORF U(L)41 encodes a protein (virion host shutoff or vhs) associated with selective degradation of mRNA early in infection [8].
  • We conclude that (i) three virion proteins are capable of binding RNA; (ii) the packaged RNA can be expressed in newly infected cells; and (iii) the U(L)47 protein was earlier reported to shuttle from nucleus to the cytoplasm and may transport RNA [9].
  • Several laboratories have shown that transfected plasmid DNAs containing either of the two known origins of herpes simplex virus (HSV) DNA replication, oriS or oriL, are replicated in HSV-1-infected cells or in cells cotransfected with virion DNA [10].

Chemical compound and disease context of US11

  • By microinjecting purified glutathione S-transferase linked to all or parts of herpes simplex virus type 1 US11 protein into either the nucleus or the cytoplasm, we have demonstrated that this nucleolar protein exhibits a new type of localization signal controlling both retention in nucleoli and export to the cytoplasm [11].
  • A herpes simplex virus 1 US11-expressing cell line is resistant to herpes simplex virus infection at a step in viral entry mediated by glycoprotein D [12].
  • To test this possibility, we engineered a peptide with affinity for immobilized cobalt in frame in the heparan sulfate binding domain of HSV-1 glycoprotein B, which is known to be exposed on the surface of the virion particle and recombined into the viral genome [13].
  • These results show for the first time that sialic acids on HSV-1 virions play an important role in infection and suggest that targeting virion sialic acids may be a valid antiviral drug development strategy [14].
  • To provide a means of investigating the activity of VP16 on IE promoters not located in the HSV-1 genome, cell lines containing the neomycin phosphotransferase gene controlled by the HSV-1 IE ICPO promoter were constructed [15].

Biological context of US11


Anatomical context of US11

  • We propose a model for infectious entry of HSV-1 by a series of interactions between the virion envelope and the cell plasma membrane that trigger virion disassembly, membrane fusion, and capsid penetration [18].
  • The site of the defect in retrograde spread remains to be determined; however, infection of rat superior cervical ganglia neurons in vitro indicates that gE is required to target virion components to the axon initial segment [19].
  • A baby hamster kidney [BHK(tk-)] cell line (US11cl19) which stably expresses the US11 and alpha 4 genes of herpes simplex virus 1 strain F [HSV-1(F)] was found to be resistant to infection with HSV-1 [12].
  • US11 localizes to the nucleolus in infected cells, can associate with ribosomes, and has been shown to bind RNA [20].
  • Input virion-associated VP13/14 and VP16 localized to the nucleus early in infection, while VP1/2 localized to the nuclear envelope of the cell and VP22 could not be detected using monoclonal antibody P43 [21].

Associations of US11 with chemical compounds

  • US11 binding protected the consensus motif from hydroxyl radical cleavage [1].
  • Oncolysis by a replicating HSV-1 mutant combined with therapeutic transgene delivery represents a new paradigm; HSV1yCD-infected cells are destroyed by viral replication, and uninfected cells are subjected to bystander killing from both progeny virion and extracellular diffusion of 5-FU [22].
  • We confirmed that gB, gC, and gD could be cross-linked to each other on the virion surface but found that the absence of one glycoprotein did not alter the outcome of cross-linking reactions between the remaining molecules [23].
  • Entry was not inhibited by bafilomycin A1 or ammonium chloride, showing that passage of the virion through a low-pH environment was not required for infection [24].
  • In the presence of Roscovitine, the level of virion-induced activation of a transfected reporter gene (the gene encoding chloramphenicol acetyltransferase) linked to the promoter-regulatory region of the ICP0 gene was reduced 40-fold relative to that of untreated samples [25].

Regulatory relationships of US11

  • These experiments revealed that this interaction has biological activity; at early times of infection, US11 down-regulates UL13 protein kinase mRNA and protein [20].

Other interactions of US11

  • To elucidate the role of US11 in the virus life cycle, we infected cells with wild-type virus, a cosmid-reconstructed US11 HSV-1 null mutant, and a cosmid-reconstructed wild-type virus and analyzed expression of UL12, -13, and -14 during a time course of infection [20].
  • US1.5 protein must be posttranslationally modified by the UL13 protein kinase to enable expression of a subset of late genes exemplified by UL38 and US11 [26].
  • Intercellular trafficking and cytotoxicity of recombinant HSV-1 thymidine kinase fused with HSV-2 US11 RXP repeat peptide [27].
  • Gene UL11 of herpes simplex virus type 1 encodes a virion protein which is myristylated [28].

Analytical, diagnostic and therapeutic context of US11


  1. Binding of herpes simplex virus-1 US11 to specific RNA sequences. Bryant, K.F., Cox, J.C., Wang, H., Hogle, J.M., Ellington, A.D., Coen, D.M. Nucleic Acids Res. (2005) [Pubmed]
  2. Herpes simplex virus type 1 UL46 and UL47 deletion mutants lack VP11 and VP12 or VP13 and VP14, respectively, and exhibit altered viral thymidine kinase expression. Zhang, Y., McKnight, J.L. J. Virol. (1993) [Pubmed]
  3. The myristylated virion proteins of herpes simplex virus type 1: investigation of their role in the virus life cycle. MacLean, C.A., Dolan, A., Jamieson, F.E., McGeoch, D.J. J. Gen. Virol. (1992) [Pubmed]
  4. Noninfectious L-particles supply functions which can facilitate infection by HSV-1. McLauchlan, J., Addison, C., Craigie, M.C., Rixon, F.J. Virology (1992) [Pubmed]
  5. Regulation of herpes simplex virus true late gene expression: sequences downstream from the US11 TATA box inhibit expression from an unreplicated template. Kibler, P.K., Duncan, J., Keith, B.D., Hupel, T., Smiley, J.R. J. Virol. (1991) [Pubmed]
  6. Native hepatitis B virions and capsids visualized by electron cryomicroscopy. Dryden, K.A., Wieland, S.F., Whitten-Bauer, C., Gerin, J.L., Chisari, F.V., Yeager, M. Mol. Cell (2006) [Pubmed]
  7. CD8(+) T cells can block herpes simplex virus type 1 (HSV-1) reactivation from latency in sensory neurons. Liu, T., Khanna, K.M., Chen, X., Fink, D.J., Hendricks, R.L. J. Exp. Med. (2000) [Pubmed]
  8. The U(L)41 protein of herpes simplex virus 1 degrades RNA by endonucleolytic cleavage in absence of other cellular or viral proteins. Taddeo, B., Zhang, W., Roizman, B. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  9. Of the three tegument proteins that package mRNA in herpes simplex virions, one (VP22) transports the mRNA to uninfected cells for expression prior to viral infection. Sciortino, M.T., Taddeo, B., Poon, A.P., Mastino, A., Roizman, B. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  10. A method for identifying the viral genes required for herpesvirus DNA replication. Challberg, M.D. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  11. Unique motif for nucleolar retention and nuclear export regulated by phosphorylation. Catez, F., Erard, M., Schaerer-Uthurralt, N., Kindbeiter, K., Madjar, J.J., Diaz, J.J. Mol. Cell. Biol. (2002) [Pubmed]
  12. A herpes simplex virus 1 US11-expressing cell line is resistant to herpes simplex virus infection at a step in viral entry mediated by glycoprotein D. Roller, R.J., Roizman, B. J. Virol. (1994) [Pubmed]
  13. Immobilized cobalt affinity chromatography provides a novel, efficient method for herpes simplex virus type 1 gene vector purification. Jiang, C., Wechuck, J.B., Goins, W.F., Krisky, D.M., Wolfe, D., Ataai, M.M., Glorioso, J.C. J. Virol. (2004) [Pubmed]
  14. Sialic Acid on herpes simplex virus type 1 envelope glycoproteins is required for efficient infection of cells. Teuton, J.R., Brandt, C.R. J. Virol. (2007) [Pubmed]
  15. Inhibition of herpes simplex virus type 1 immediate-early gene expression by alpha interferon is not VP16 specific. Nicholl, M.J., Preston, C.M. J. Virol. (1996) [Pubmed]
  16. Phosphorylation of structural components promotes dissociation of the herpes simplex virus type 1 tegument. Morrison, E.E., Wang, Y.F., Meredith, D.M. J. Virol. (1998) [Pubmed]
  17. Expression of the herpes simplex virus 1 alpha transinducing factor (VP16) does not induce reactivation of latent virus or prevent the establishment of latency in mice. Sears, A.E., Hukkanen, V., Labow, M.A., Levine, A.J., Roizman, B. J. Virol. (1991) [Pubmed]
  18. Herpes simplex virus type 1 entry through a cascade of virus-cell interactions requires different roles of gD and gH in penetration. Fuller, A.O., Lee, W.C. J. Virol. (1992) [Pubmed]
  19. Herpes simplex virus type 1 glycoprotein e is required for axonal localization of capsid, tegument, and membrane glycoproteins. Wang, F., Tang, W., McGraw, H.M., Bennett, J., Enquist, L.W., Friedman, H.M. J. Virol. (2005) [Pubmed]
  20. The herpes simplex virus type 1 US11 protein binds the coterminal UL12, UL13, and UL14 RNAs and regulates UL13 expression in vivo. Attrill, H.L., Cumming, S.A., Clements, J.B., Graham, S.V. J. Virol. (2002) [Pubmed]
  21. Differences in the intracellular localization and fate of herpes simplex virus tegument proteins early in the infection of Vero cells. Morrison, E.E., Stevenson, A.J., Wang, Y.F., Meredith, D.M. J. Gen. Virol. (1998) [Pubmed]
  22. Multimodality therapy with a replication-conditional herpes simplex virus 1 mutant that expresses yeast cytosine deaminase for intratumoral conversion of 5-fluorocytosine to 5-fluorouracil. Nakamura, H., Mullen, J.T., Chandrasekhar, S., Pawlik, T.M., Yoon, S.S., Tanabe, K.K. Cancer Res. (2001) [Pubmed]
  23. Assembly and organization of glycoproteins B, C, D, and H in herpes simplex virus type 1 particles lacking individual glycoproteins: No evidence for the formation of a complex of these molecules. Rodger, G., Boname, J., Bell, S., Minson, T. J. Virol. (2001) [Pubmed]
  24. Glycoprotein D receptor-dependent, low-pH-independent endocytic entry of herpes simplex virus type 1. Milne, R.S., Nicola, A.V., Whitbeck, J.C., Eisenberg, R.J., Cohen, G.H. J. Virol. (2005) [Pubmed]
  25. Transactivation of herpes simplex virus type 1 immediate-early gene expression by virion-associated factors is blocked by an inhibitor of cyclin-dependent protein kinases. Jordan, R., Schang, L., Schaffer, P.A. J. Virol. (1999) [Pubmed]
  26. Functional anatomy of herpes simplex virus 1 overlapping genes encoding infected-cell protein 22 and US1.5 protein. Ogle, W.O., Roizman, B. J. Virol. (1999) [Pubmed]
  27. Intercellular trafficking and cytotoxicity of recombinant HSV-1 thymidine kinase fused with HSV-2 US11 RXP repeat peptide. Luo, C., Nawa, A., Yamauchi, Y., Kohno, S., Ushijima, Y., Goshima, F., Kikkawa, F., Nishiyama, Y. Virus Genes (2007) [Pubmed]
  28. Gene UL11 of herpes simplex virus type 1 encodes a virion protein which is myristylated. MacLean, C.A., Clark, B., McGeoch, D.J. J. Gen. Virol. (1989) [Pubmed]
  29. RNAs extracted from herpes simplex virus 1 virions: apparent selectivity of viral but not cellular RNAs packaged in virions. Sciortino, M.T., Suzuki, M., Taddeo, B., Roizman, B. J. Virol. (2001) [Pubmed]
  30. Study of herpes simplex virus maturation during a synchronous wave of assembly. Church, G.A., Wilson, D.W. J. Virol. (1997) [Pubmed]
  31. General and specific alterations in programming of global viral gene expression during infection by VP16 activation-deficient mutants of herpes simplex virus type 1. Yang, W.C., Devi-Rao, G.V., Ghazal, P., Wagner, E.K., Triezenberg, S.J. J. Virol. (2002) [Pubmed]
  32. Site-directed mutagenesis of the virion host shutoff gene (UL41) of herpes simplex virus (HSV): analysis of functional differences between HSV type 1 (HSV-1) and HSV-2 alleles. Everly, D.N., Read, G.S. J. Virol. (1999) [Pubmed]
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