Projects / Programmes
Role of sumoylation in Human Papillomavirus (HPV) induced carcinogenesis
| Code |
Science |
Field |
Subfield |
| 1.05.00 |
Natural sciences and mathematics |
Biochemistry and molecular biology |
|
| Code |
Science |
Field |
| B230 |
Biomedical sciences |
Microbiology, bacteriology, virology, mycology |
sumoylation, Human Papillomavirus (HPV), cervical cancer, HPV proteins
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
21192 |
PhD Helena Šterlinko Grm |
Biochemistry and molecular biology |
Head |
2007 - 2009 |
33 |
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
1540 |
University of Nova Gorica |
Nova Gorica |
5920884000 |
14,072 |
Abstract
Human Papillomaviruses (HPV) are important human pathogens. When these viruses infect cutaneous or mucosal epithelium they can initially cause clinical warts or persistent infection with little or no visible manifestations. Furthermore, infection with certain specific HPV types, such as 16 or 18, is the major risk factor for a woman’s development of cervical cancer, which constitutes up to 25% of all female cancers, and is the most common cancer in developing countries. Among all Human Papillomavirus (HPV) types known, type 16, 18, 31, and 45 are most often found within the malignant cells of cervical cancers, accounting for approximately 99.7% of all cervical squamous cell cancer cases. Prevention or elimination of HPV infections would not only benefit the numerous patients with benign lesions, but ultimately should reduce the incidence of cervical cancer and possibly other epithelial cancers as well. Unfortunately, no specific anti-papillomavirus agents are available so current therapy for these infections is directed primarily at physical destruction of infected tissues. The rational development of effective anti-papillomaviral compounds should be based on an understanding of the basic biology of these viruses in the host cell. Hence, we will address the SUMO modification and its role in controlling the functional properties of proteins encoded by the HPV. Sumoylation is recently discovered host cell post-translational modification system. Sumoylation is an enzymatic process that is biochemically analogous to, but functionally distinct from ubiquitination. As in ubiquitinylation, sumoylation involves the attachment of a small moiety, SUMO, to substrate proteins. Conjugation of SUMO does not typically lead to degradation of the substrate and instead causes functional alterations or changes in intracellular localisation. While the majority of identified SUMO targets are cellular proteins, Herpesvirus, Adenovirus and Papillomavirus proteins have also been identified as authentic substrates for this modification. The exact effect of sumoylation on viral proteins appears to be substrate specific, but does have functional consequences that are likely to be important for the viral life cycle. In addition to viral proteins being targets for sumoylation, there is both direct and indirect evidence that viruses can alter the sumoylation status of host cell proteins. Such modulation of critical host proteins may be important for inhibiting cellular defence mechanisms or for promoting and intracellular state that is supportive of viral replication. Detailed understanding of the sumoylation system and its role in HPV viral infection, which will be the goal of this study, could provide a wealth of information on central pathways regulating the HPV life cycle and hence offer new therapeutics aimed at the treatment of viral infection and virus-induced cancers.
Significance for science
Post-translational modifications are only one of the ways in how the cell controls its pathways. The sumoylation was recently discovered and hence both the mechanism of action and its effect on substrate proteins are still not well known. Viruses as invader of cells and usurpers of cellular machinery represent a very good tool for study host biochemical pathways. In this study we will use the proteins of Human Papillomavirus, which is an important human pathogen, shown to be also a causative agent of cancer in uterine cervix.
We supposed that the data obtained in this study will provide important informations on three different areas of research:
1.By analysing the sumoylation status of different HPV proteins and affect on their functions, which are important for the propagation of the virus, we will be able to obtain new data regarding the regulation of viral life.
We show that L2 alters the sumoylation status of the host cell by upregulating the expression levels of SUMO-2/3, but not the SUMO-1. This is the first example of a viral protein that specifically upregulates the expression of SUMO-2/3 proteins. Interestingly, upregulation of SUMO expression has also been shown during keratinocyte differentiation, the natural environment for the HPV life cycle. It has been speculated that increased SUMO-2/3 sumoylation in the infected keratinocytes could lead to HPV E2 stabilization and higher protein concentrations required for productive viral genome amplification. However, the increase in SUMO-2/3 expression appears to be short lived, and it is therefore possible that one of L2s functions is to maintain a high SUMO-2/3 level of expression, and hereby contribute to late stages of viral replication.
2.By discovering and better understanding of specific function for different HPV proteins, we could offer new and better therapeutics for the treatment of viral infection and virus-induced cancers.
At this point we cannot suggest new therapeutic approaches, however our results will contribute to the development of those. It was shown that during initial papillomavirus infection, it is L2 that accompanies the viral genome into the nucleus and traffics to PODs. We provide evidence that L2 proteins from low risk (HPV 11) and high-risk (HPV 16) types each target different PML isoforms. Our results also demonstrate that POD structures have different PML compositions and suggest that targeting specific PML isoforms might be associated with different outcomes of an HPV infection.
The first generation of profilactic vaccines is based on the HPV L1 protein, which induce predominately type-specific neutralizing antibodies. In contrast to the type-specific nature of the L1 neutralization epitopes, immunogens composed of full-length versions of the minor capsid protein L2, or highly conserved N-terminal peptides of L2, induce remarkably broad cross-type neutralizing antibodies. Recently a crossneutralizing B-cell epitope has been mapped to residues 17–36 of HPV16 L2. We showed that the sumoylation site lies between this epitope.
3.Investigating the sumoylation status of cellular proteins in the presence of different HPV proteins could help to understand better this recently discovered post-translation modification.
Our data show that the sumoylation causes the stabilization of the target protein, which was already known. New functions linked to the sumoylation were not discovered.
Significance for the country
We supposed the following advantages for the Republic of Slovenia:
1.At the possibility of a new therapy for the HPV infection the Slovenian pharmaceutical companies could gain an important advantage.
At this point we cannot suggest new therapeutic approaches, however our results will contribute to the development of those.
2.New important discoveries would strongly improve the knowledge not only about the HPV viral life cycle, but also about the sumoylation itself and its importance for the cellular pathways, adding to the Republic of Slovenia the international reputation.
We show for the first time that the viral proteins can specifically upregulate the expression levels of various components of the sumoylation system and affect the sumoylation status of their host.
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