The X-Linked Tumor Suppressor TSPX Interacts and Promotes Degradation of the Hepatitis B Viral Protein HBx via the Proteasome Pathway

Tatsuo Kido,Yun-Fai Chris Lau,Jing-Hsiung James Ou,Ben C B Ko

doi:10.1371/journal.pone.0022979

Abstract

Hepatitis B virus (HBV) infection is a major risk for hepatocellular carcinoma (HCC), and it is a serious global health problem with two billion people exposed to it worldwide. HBx, an essential factor for viral replication and a putative oncoprotein encoded by the HBV genome, has been shown to promote oncogenic properties at multiple sites in HBV-infected liver cells. The expression level of HBx closely associates with the development and progression of HCC, therefore the mechanism(s) regulating the stability of HBx is important in oncogenesis of HBV-infected cells. We demonstrate that the X-linked tumor suppressor TSPX enhances the degradation of HBx through the ubiquitin-proteasome pathway. TSPX interacts with both HBx and a proteasome 19S lid subunit RPN3 via its C-terminal acidic tail. Most importantly, over-expression of RPN3 protects HBx from, and hence acts as a negative regulator for, proteasome-dependent degradation. TSPX abrogates the RPN3-depedent stabilization of HBx, suggesting that TSPX and RPN3 act competitively in regulation of HBx stability. Since mutation and/or epigenetic repression of X-located tumor suppressor gene(s) could significantly predispose males to human cancers, our data suggest that TSPX-induced HBx degradation could play key role(s) in hepatocarcinogenesis among HBV-infected HCC patients.

Highlights

The Y-encoded testis-specific protein Y-encoded (TSPY) and its X-chromosome homologue TSPX are members of the SET/NAP1 superfamily of proteins, which are characterized by the presence of a highly conserved NAP-domain [1,2,3]
(,50%) [8], and HBV X protein (HBx) stability and actions are closely associated with hepatocellular carcinoma (HCC) development, we had examined the probable functions of TSPY and its X-linked homologue TSPX in Hepatitis B virus (HBV)-mediated HCC
Our results showed that when HA-HBx was co-transfected with TSPX, the levels of HA-HBx protein were significantly repressed (Figure 1B) while no significant change was observed in the cells co-transfected with TSPY expression vectors (Figure S1)

Summary

Introduction

The Y-encoded testis-specific protein Y-encoded (TSPY) and its X-chromosome homologue TSPX ( called TSPYL2, CDA1 and DENTT) are members of the SET/NAP1 superfamily of proteins, which are characterized by the presence of a highly conserved NAP-domain [1,2,3]. TSPY interacts with cyclin BCDK1 complex and stimulates its kinase activities and accelerates G2/M transition of the host cells [11] It binds the translation elongation factor eEF1A and promotes cellular protein synthesis, an essential oncogenic property of a cancer cell [12]. It is considered as a X-linked tumor suppressor These observations suggest that, TSPY and TSPX originated from the same ancestor gene, they play opposite roles in regulation of cell proliferation and tumorigenesis. Such contrasting properties of a pair of sex chromosome homologues raise the possibility that they might play important roles in sexual dimorphisms in certain somatic cancers, such as hepatocellular carcinoma, which significantly affects more men than women among their respective patient populations

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