A Comprehensive Proteomics Analysis of the JC Virus (JCV) Large and Small Tumor Antigen Interacting Proteins: Large T Primarily Targets the Host Protein Complexes with V-ATPase and Ubiquitin Ligase Activities While Small t Mostly Associates with Those Having Phosphatase and Chromatin-Remodeling Functions.

Sami Saribas,Mahmut Safak

doi:10.3390/v12101192

Abstract

The oncogenic potential of both the polyomavirus large (LT-Ag) and small (Sm t-Ag) tumor antigens has been previously demonstrated in both tissue culture and animal models. Even the contribution of the MCPyV tumor antigens to the development of an aggressive human skin cancer, Merkel cell carcinoma, has been recently established. To date, the known primary targets of these tumor antigens include several tumor suppressors such as pRb, p53, and PP2A. However, a comprehensive list of the host proteins targeted by these proteins remains largely unknown. Here, we report the first interactome of JCV LT-Ag and Sm t-Ag by employing two independent “affinity purification/mass spectroscopy” (AP/MS) assays. The proteomics data identified novel targets for both tumor antigens while confirming some of the previously reported interactions. LT-Ag was found to primarily target the protein complexes with ATPase (v-ATPase and Smc5/6 complex), phosphatase (PP4 and PP1), and ligase (E3-ubiquitin) activities. In contrast, the major targets of Sm t-Ag were identified as Smarca1/6, AIFM1, SdhA/B, PP2A, and p53. The interactions between “LT-Ag and SdhB”, “Sm t-Ag and Smarca5”, and “Sm t-Ag and SDH” were further validated by biochemical assays. Interestingly, perturbations in some of the LT-Ag and Sm t-Ag targets identified in this study were previously shown to be associated with oncogenesis, suggesting new roles for both tumor antigens in novel oncogenic pathways. This comprehensive data establishes new foundations to further unravel the new roles for JCV tumor antigens in oncogenesis and the viral life cycle.

Highlights

Viruses are all obligatory intracellular parasites due to their limited genomic coding capacity.A number of proteins encoded by their small genomes are insufficient to form a host-independent organism
Since JCV genome was detected in various human tumors [150,151,152,153], it is suggested that the oncogenic tumor antigens of JCV could play a role in the induction of some of the human tumors, as seen by those of
In an attempt to further unravel their cellular targets and thereby open new avenues to explore their oncogenic mechanisms, in this work, we employed a proteomics approach to identify the partners of both proteins in cells

Summary

Introduction

Viruses are all obligatory intracellular parasites due to their limited genomic coding capacity.A number of proteins encoded by their small genomes are insufficient to form a host-independent organism. We have learned much about the mechanisms of the cell transformation by studying the oncogenic properties of various viral proteins encoded by these viruses [4,5]. The second (mouse polyomavirus) [8] and the third (simian virus-40 (SV40)) [9] oncogenic viruses were isolated from the mouse-derived leukemic extracts and the monkey renal culture cells, respectively. These last two oncogenic viruses were of animal origin and classified under a new virus family, polyomaviruses, during the early 1950s and 1960s, respectively. The first two human polyomaviruses (JC virus (JCV) and BK virus (BKV)) were discovered approximately

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Conclusion