Technical discussion of papillomavirus gene functions edit
Genes within the papillomavirus genome are usually identified after similarity with other previously identified genes. However, some spurious open reading frames might have been mistaken as genes simply after their position in the genome, and might not be true genes. This applies specially to certain E3, E4, E5 and E8 open reading frames.
E1 edit
Encodes a protein that binds to the viral origin of replication in the long control region of the viral genome. E1 uses ATP to exert a helicase activity that forces apart the DNA strands, thus preparing the viral genome for replication by cellular DNA replication factors.
E2 edit
The E2 protein serves as a master transcriptional regulator for viral promoters located primarily in the long control region. The protein has a transactivation domain linked by a relatively unstructured hinge region to a well-characterized DNA binding domain. E2 facilitates the binding of E1 to the viral origin of replication. E2 also utilizes a cellular protein known as Bromodomain-4 (Brd4) to tether the viral genome to cellular chromosomes.[1] This tethering to the cell's nuclear matrix ensures faithful distribution of viral genomes to each daughter cell after cell division. It is thought that E2 serves as a negative regulator of expression for the oncogenes E6 and E7 in latently HPV-infected basal layer keratinocytes. Genetic changes, such as integration of the viral DNA into a host cell chromosome, that inactivate E2 expression tend to increase the expression of the E6 and E7 oncogenes, resulting in cellular transformation and possibly further genetic destabilization.
E3 edit
This small putative gene exists only in a few papillomavirus types. The gene is not known to be expressed as a protein and does not appear to serve any function.
E4 edit
Although E4 proteins are expressed at low levels during the early phase of viral infection, expression of E4 increases dramatically during the late phase of infection. In other words, its “E” appellation may be something of a misnomer. In the case of HPV-1, E4 can account for up to 30% of the total protein at the surface of a wart.[2] The E4 protein of many papillomavirus types is thought to facilitate virion release into the environment by disrupting intermediate filaments of the keratinocyte cytoskeleton. Viral mutants incapable of expressing E4 do not support high-level replication of the viral DNA, but it is not yet clear how E4 facilitates DNA replication. E4 has also been shown to participate in arresting cells in the G2 phase of the cell cycle.
E5 edit
The E5 are small, very hydrophobic proteins that destabilise the function of many membrane proteins in the infected cell.[3] The E5 protein of some animal papillomavirus types (mainly bovine papillomavirus type 1) functions as an oncogene primarily by activating the cell growth-promoting signaling of platelet-derived growth factor receptors. The E5 proteins of human papillomaviruses associated to cancer, however, seem to activate the signal cascade initiated by epidermal growth factor upon ligand binding. HPV16 E5 and HPV2 E5 have also been shown to down-regulate the surface expression of major histocompatibility complex class I proteins, which may prevent the infected cell from being eliminated by killer T cells.
E6 edit
E6 is a 151 amino-acid peptide that incorporates a type 1 motif with a consensus sequence –(T/S)-(X)-(V/I)-COOH.[4][5] It also has two zinc finger motifs.[4]
E6 is of particular interest because it appears to have multiple roles in the cell and to interact with many other proteins. Its major role, however, is to mediate the degradation of p53, a major tumor suppressor protein, reducing the cell's ability to respond to DNA damage. [6][7]
E6 has also been shown to target other cellular proteins, thereby altering several metabolic pathways. One such target is NFX1-91, which normally represses production of telomerase, a protein that allows cells to divide an unlimited number of times. When NFX1-91 is degraded by E6, telomerase levels increase, inactivating a major mechanism keeping cell growth in check.[8] Additionally, E6 can act as a transcriptional cofactor—specifically, a transcription activator—when interacting with the cellular transcription factor, E2F1/DP1.[4]
E6 can also bind to PDZ-domains, short sequences which are often found in signaling proteins. E6's structural motif allows for interaction with PDZ domains on DLG (discs large) and hDLG (Drosophila large) tumor suppressor genes.[5][9] Binding at these locations causes transformation of the DLG protein and disruption of its suppressor function. E6 proteins also interact with the MAGUK (membrane-associated guanylate kinase family) proteins. These proteins, including MAGI-1, MAGI-2, and MAGI-3 are usually structural proteins, and can help with signaling.[5][9] More significantly, they are believed to be involved with DLG's suppression activity. When E6 complexes with the PDZ domains on the MAGI proteins, it distorts their shape and thereby impedes their function. Overall, the E6 protein serves to impede normal protein activity in such a way as to allow a cell to grow and multiply at the increased rate characteristic of cancer.
Since the expression of E6 is strictly required for maintenance of a malignant phenotype in HPV-induced cancers, it is an appealing target of therapeutic HPV vaccines designed to eradicate established cervical cancer tumors.
E7 edit
In most papillomavirus types, the primary function of the E7 protein is to inactivate members of the pRb family of tumor suppressor proteins. Together with E6, E7 serves to prevent cell death (apoptosis) and promote cell cycle progression, thus priming the cell for replication of the viral DNA. E7 also participates in immortalization of infected cells by activating cellular telomerase. Like E6, E7 is the subject of intense research interest and is believed to exert a wide variety of other effects on infected cells. As with E6, the ongoing expression of E7 is required for survival of cancer cell lines, such as HeLa, that are derived from HPV-induced tumors.[10]
E8 edit
Only a few papillomavirus types encode a short protein from the E8 gene. In the case of BPV-4 (papillomavirus genus Xi), the E8 open reading frame may substitute for the E6 open reading frame, which is absent in this papillomavirus genus.[11] These E8 genes are chemically and functionally similar to the E5 genes from some human papillomaviruses, and are also called E5/E8.
L1 edit
L1 spontaneously self-assembles into pentameric capsomers. Purified capsomers can go on to form capsids, which are stabilized by disulfide bonds between neighboring L1 molecules. L1 capsids assembled in vitro are the basis of prophylactic vaccines against several HPV types. Compared to other papillomavirus genes, the amino acid sequences of most portions of L1 are well-conserved between types. However, the surface loops of L1 can differ substantially, even for different members of a particular papillomavirus species. This probably reflects a mechanism for evasion of neutralizing antibody responses elicited by previous papillomavirus infections.[12]
L2 edit
L2 exists in an oxidized state within the papillomavirus virion, with the two conserved cysteine residues forming an intramolecular disulfide bond.[13] In addition to cooperating with L1 to package the viral DNA into the virion, L2 has been shown to interact with a number of cellular proteins during the infectious entry process. After the initial binding of the virion to the cell, L2 must be cleaved by the cellular protease furin.[14] The virion is internalized, probably through a clathrin-mediated process, into an endosome, where acidic conditions are thought to lead to exposure of membrane-destabilizing portions of L2.[15] The cellular proteins beta-actin[16] and syntaxin-18[17] may also participate in L2-mediated entry events. After endosome escape, L2 and the viral genome are imported into the cell nucleus where they traffic to a sub-nuclear domain known as an ND-10 body that is rich in transcription factors.[18] Small portions of L2 are well-conserved between different papillomavirus types, and experimental vaccines targeting these conserved domains may offer protection against a broad range of HPV types.[19]
References edit
- ^ McBride AA, McPhillips MG, Oliveira JG (2004). "Brd4: tethering, segregation and beyond". Trends Microbiol. 12 (12): 527–9. doi:10.1016/j.tim.2004.10.002. PMID 15539109.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Doorbar J, Campbell D, Grand RJ, Gallimore PH (1986). "Identification of the human papilloma virus-1a E4 gene products". EMBO J. 5 (2): 355–62. PMC 1166739. PMID 3011404.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Bravo IG, Alonso A (2004). "Mucosal human papillomaviruses encode four different E5 proteins whose chemistry and phylogeny correlate with malignant or benign growth". J. Virol. 78 (24): 13613–26. doi:10.1128/JVI.78.24.13613-13626.2004. PMC 533923. PMID 15564472.
- ^ a b c Gupta S, Takhar PP, Degenkolbe R, Koh CH, Zimmermann H, Yang CM, Guan Sim K, Hsu SI, Bernard HU (2003). "The human papillomavirus type 11 and 16 E6 proteins modulate the cell-cycle regulator and transcription cofactor TRIP-Br1" ([dead link] – Scholar search). Virology. 317 (1): 155–64. doi:10.1016/j.virol.2003.08.008. PMID 14675634.
{{cite journal}}: External link in|format= - ^ a b c Glaunsinger BA, Lee SS, Thomas M, Banks L, Javier R (2000). "Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins". Oncogene. 19 (46): 5270–80. doi:10.1038/sj.onc.1203906. PMID 11077444.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ "iHOP information Hyperlinked over Proteins UBE3A". Retrieved 2007-05-01.
- ^ "Biochemistry, Nottingham University - 3.0 Enzymes of the Ubiquitin Pathway". Retrieved 2007-05-01.
- ^ Kelley ML, Keiger KE, Lee CJ, Huibregtse JM (2005). "The global transcriptional effects of the human papillomavirus E6 protein in cervical carcinoma cell lines are mediated by the E6AP ubiquitin ligase". J. Virol. 79 (6): 3737–47. doi:10.1128/JVI.79.6.3737-3747.2005. PMC 1075713. PMID 15731267.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ a b Kiyono T, Hiraiwa A, Fujita M, Hayashi Y, Akiyama T, Ishibashi M (1997). "Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor protein". Proc. Natl. Acad. Sci. U.S.A. 94 (21): 11612–6. doi:10.1073/pnas.94.21.11612. PMC 23554. PMID 9326658.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Nishimura A, Nakahara T, Ueno T; et al. (2006). "Requirement of E7 oncoprotein for viability of HeLa cells". Microbes Infect. 8 (4): 984–93. doi:10.1016/j.micinf.2005.10.015. PMID 16500131.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - ^ Jackson ME, Pennie WD, McCaffery RE, Smith KT, Grindlay GJ, Campo MS (1991). "The B subgroup bovine papillomaviruses lack an identifiable E6 open reading frame". Mol. Carcinog. 4 (5): 382–7. doi:10.1002/mc.2940040510. PMID 1654923.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Carter JJ, Wipf GC, Madeleine MM, Schwartz SM, Koutsky LA, Galloway DA (2006). "Identification of human papillomavirus type 16 L1 surface loops required for neutralization by human sera". J. Virol. 80 (10): 4664–72. doi:10.1128/JVI.80.10.4664-4672.2006. PMC 1472072. PMID 16641259.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Campos SK, Ozbun MA (2009). "Two highly conserved cysteine residues in HPV16 L2 form an intramolecular disulfide bond and are critical for infectivity in human keratinocytes". PLoS ONE. 4 (2): e4463. doi:10.1371/journal.pone.0004463. PMC 2636891. PMID 19214230.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Richards RM, Lowy DR, Schiller JT, Day PM (2006). "Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection". Proc. Natl. Acad. Sci. U.S.A. 103 (5): 1522–7. doi:10.1073/pnas.0508815103. PMC 1360554. PMID 16432208.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Kämper N, Day PM, Nowak T; et al. (2006). "A membrane-destabilizing peptide in capsid protein L2 is required for egress of papillomavirus genomes from endosomes". J. Virol. 80 (2): 759–68. doi:10.1128/JVI.80.2.759-768.2006. PMC 1346844. PMID 16378978.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - ^ Yang R, Yutzy WH, Viscidi RP, Roden RB (2003). "Interaction of L2 with beta-actin directs intracellular transport of papillomavirus and infection". J. Biol. Chem. 278 (14): 12546–53. doi:10.1074/jbc.M208691200. PMID 12560332.
{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ Bossis I, Roden RB, Gambhira R; et al. (2005). "Interaction of tSNARE syntaxin 18 with the papillomavirus minor capsid protein mediates infection". J. Virol. 79 (11): 6723–31. doi:10.1128/JVI.79.11.6723-6731.2005. PMC 1112158. PMID 15890910.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - ^ Day PM, Baker CC, Lowy DR, Schiller JT (2004). "Establishment of papillomavirus infection is enhanced by promyelocytic leukemia protein (PML) expression". Proc. Natl. Acad. Sci. U.S.A. 101 (39): 14252–7. doi:10.1073/pnas.0404229101. PMC 521143. PMID 15383670.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Pastrana DV, Gambhira R, Buck CB; et al. (2005). "Cross-neutralization of cutaneous and mucosal Papillomavirus types with anti-sera to the amino terminus of L2". Virology. 337 (2): 365–72. doi:10.1016/j.virol.2005.04.011. PMID 15885736.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link)