Essential role of HCMV deubiquitinase in promoting oncogenesis by targeting anti-viral innate immune signaling pathways

Puja Kumari,Irene Saha,Athira Narayanan,Sathish Narayanan,Nachimuthu Senthil Kumar,Himanshu Kumar,Prafullakumar Tailor,Akinori Takaoka

doi:10.1038/cddis.2017.461

Abstract

Cancer is a multifactorial disease and virus-mediated carcinogenesis is one of the crucial factors, which is poorly understood. Human cytomegalovirus (HCMV) is a herpesvirus and its components have been evidenced to be associated with cancer of different tissue origin. However, its role in cancer remains unknown. Here, we identified a conserved herpesviral tegument protein known as pUL48 of HCMV, encoding deubiquitinase enzyme, as having a key role in carcinogenesis. We show using deubiquitinase sufficient- and deficient-HCMV that HCMV deubiquitinase is a key in inducing enhanced cellular metabolic activity through upregulation of several anti-apoptotic genes and downregulation of several pro-apoptotic genes expression. Furthermore, HCMV deubiquitinase acquires pro-tumor functions by inhibiting PRR-mediated type I interferon via deubiquitination of TRAF6, TRAF3, IRAK1, IRF7 and STING. Taken together, our results suggest that HCMV infection may promote oncogenesis by inhibiting innate immunity of the host.

Highlights

Cancer is a multifactorial disease causing death worldwide and proves to be a burden on human health
Differential expression of antiand pro-apoptotic genes during WT-Human cytomegalovirus (HCMV)- and ΔDUBHCMV infection indicates that HCMV-pUL48 DUB activity interferes with the induction of apoptosis and may induce oncogenic properties. Consistent with this interpretation, we found that the ability of anti-cancer drug etoposide to promote apoptosis, was reduced by wild-type HCMV (WT-HCMV) infection but not by ΔDUB-HCMV infection (Figure 3d)
Our study suggests that as a consequence of overcoming anti-viral innate immune response, HCMV infection and enzymatic activity of the HCMV-DUB, in particular, may initiate early steps in oncogenesis (Figure 7)

Summary

Introduction

Cancer is a multifactorial disease causing death worldwide and proves to be a burden on human health. HCMV infection is mostly asymptomatic due to host anti-viral immunity, it may lead to oncogenic transformation of normal cells and cancer, when host is immunocompromised owing to immunosuppressive drugs or infection with HIV. Cellular DUBs have an important role in many signaling pathways, including immune signaling, apoptosis, oncogenesis and developmental pathways.[12,13,14] Likewise, our findings as well reveal that upon infection, HCMV-DUB inhibits synthesis of I-IFNs, an anti-cancer factor, by deubiquitinating several signaling molecules such as TNF receptor-associated factor (TRAF)-6 and -3, interleukin-1 receptor-associated kinase-1 (IRAK1), interferon regulatory factor (IRF)-7 or stimulator of interferon genes (STING) that have a key role in anti-viral innate immunity. Inhibition of I-IFNs by HCMV-DUB correlates with decreased expression of several pro-apoptotic

Methods

Results

Conclusion