Human Polyomaviruses: The Battle of Large and Small Tumor Antigens

Abstract

About 40 years ago, the large and small tumor antigens (LT-Ag and sT-Ag) of the polyomavirus (PyVs) simian vacuolating virus 40 have been identified and characterized. To date, it is well known that all the discovered human PyVs (HPyVs) encode these 2 multifunctional and tumorigenic proteins, expressed at viral replication early stage. The 2 T-Ags are able to transform cells both in vitro and in vivo and seem to play a distinct role in the pathogenesis of some tumors in humans. In addition, they are involved in viral DNA replication, transcription, and virion assembly. This short review focuses on the structural and functional features of the HPyVs' LT-Ag and sT-Ag, with special attention to their transforming properties.

Keywords: Polyomavirus; large T antigen; neoplasia; small T antigen.

Figure 1.

Scheme of the functional domains of the HPyVs’ large tumor antigen (LT-Ag). The LT-Ag consists of several functional domains: DnaJ domain, linker domain, origin-binding domain (OBD), zinc (Zn⁺⁺)-binding domain, and helicase/ATPase domain. (A) The DnaJ domain contains a HPDKGG motif, conserved among HPyVs, which is able to bind to the Hsc70, a cellular chaperone and transcriptional repressor; a CR1 motif (LXXLL), present only in BKPyV, JCPyV, and MCPyV. (B) The linker domain contains WXXWW motif, conserved in most of the HPyVs but not in MCPyV, for binding Bub1, a mitotic checkpoint serine-threonine protein kinase; a unique region (MUR), only present in MCPyV, that binds the Vamp6P-protein and the Bromodomain protein 4 for the recruitment of cellular protein factor C (RFC); a LXCXE motif, conserved in most of the HPyVs, crucial for the interaction with the retinoblastoma protein (pRb) family. (C) The helicase/ATPase domain comprises a p53-binding domain, conserved in most of the HPyVs; a C-terminal domain, only present in JCPyV, that binds the insulin receptor substrate 1 (IRF1). ATPase indicates adenosine triphosphatase; BKPyV, human BK polyomavirus; HPyVs, human polyomaviruses; JCPyV, human JC polyomavirus; MCPyV, Merkel cell polyomavirus; MUR, MCPyV T antigen unique region.

Figure 2.

HPyVs’ large tumor antigen (LT-Ag) oncogenic mechanisms. (A) In physiological conditions, the retinoblastoma proteins (pRbs) are in a hypophosphorylated state, which allows them to bind and inhibit the E2F transcription factors, preventing the E2F-mediated gene expression and consequently the transition from G₁ to S phase. HPyVs’ LT-Ag is able to bind the pRbs promoting their hyperphosphorylation, thus pRb is unable to bind E2F, leading to its transcriptional activity; at the same time, the hyperphosphorylation of p130 disrupts the transcriptional repressor complex (p130-E2F4/5), leading to uncontrolled cell cycle progression and sometimes to malignant transformation. (B) Multiple cellular stress, normally, raises the levels of p53, which promotes the DNA repair and cell cycle arrest. HPyVs’ LT-Ag is able to bind and block the activity of p53 protein, preventing apoptosis and cell cycle arrest induced by DNA damage. (C) In physiological conditions, the phosphorylated β-catenin undergoes degradation via ubiquitin-dependent proteasome. JCPyVs’ LT-Ag binds the β-catenin protein promoting its hypophosphorylation, thus β-catenin complexes with LEF-1/TCF-4 transcription factors, promoting the cell cycle progression by c-myc and cyclin D1 expression. HPyVs indicate human polyomaviruses; JCPyV, human JC polyomavirus.

Figure 3.

Scheme of the functional domains of the HPyVs’ small tumor antigen (sT-Ag). The sT-Ag presents a DnaJ domain, followed by a unique domain, that is removed from LT-Ag during the splicing process. (A) The DnaJ domain contains a LYCKE motif (JCPyV and BKPyV) and a LHCWE motif (only JCPYV), able to interact with pRb family proteins. (B) The unique domains contain 2 Zn⁺⁺-binding sites and, additionally and only in MCPyV, a PPAR1/NEMO-binding site and a large T stabilization domain (LSD) that are involved in the oncogenesis process. (C) The binding site for the PP2A is conserved in most of the HPyVs and triggers several pathways related to cellular transformation. BKPyV indicates human BK polyomavirus; HPyVs, human polyomaviruses; JCPyV, human JC polyomavirus; MCPyV, Merkel cell polyomavirus; NEMO, NF-κB essential modulator.

Figure 4.

HPyVs’ small tumor antigen (sT-Ag) oncogenic mechanisms. (A) In physiological conditions, the Akt, p53, c-Myc, and β-catenin proteins are in a phosphorylated state; the subsequent dephosphorylation due to the PP2A serine-threonine phosphatase regulates the cell cycle progression and the apoptosis process. (B) The binding between sT-Ag and PP2A avoids the dephosphorylation of Akt, p53, c-Myc, and β-catenin proteins, and the subsequent deregulation of the cell cycle progression and apoptosis process drives the cell to a malignant transformation. HPyVs indicate human polyomaviruses; PP2A, phosphatase 2A.