HBx

Abstract

HBx guaranties optimal replication conditions by overcoming host cell defenses, regulating viral replication and modulating host cell signaling pathways and genes expression. The protein has been associated with numerous functions in and out of the nucleus, and numerous protein-protein interactions.
The two main functions are: in the nucleus HBx promotes the viral minichromosome transcription, presumably linked with DDB1 interaction; in the cytoplasm HBx degrades MAVS in the mitochondria which has a potent antiviral action in hepatocytes.

If there is a protein that is not among the list of HBx interactors, then this protein has probably not yet been tested. (Murakami 2001 ) Rating=Review

General comments
The HBx protein would likely be involved in few cellular mechanism, presumably associated with mammalian specific host defense. A single interaction may trigger many phenotypes context- and cellular-dependent. For example twenty years ago the C protein of Sendai was associated with dozens of heterogenic phenotypes, binding and signaling pathways. 90% of phenotypes made sense when it was discovered that it was counteracting the interferon induced antiviral state. Most protein-protein interactions turned out to be wrong though. Indeed viral proteins being xeno-interactors, they are not subject to the selective pressure of avoiding harming the cell by binding random cellular proteins at high level of expression. This is a characteristic common to viral protein disordered regions.
Moreover a viral protein function can be misinterpreted because of a specialized function. An example is EBNA2 of Epstein-BArr virus. EBNA2 function is to prevent infected B lymphocyte suicide. But it acts as a strong oncogene when over-expressed in cell culture, and this observation complicated the understanding of its function.

The actual function of HBx could be to counteract a mammalian defense which would prevent the expression of HBV minichromosome. This HBx function would have many side effects, like incidental oncogenesis.

HBx is restrained to mammalian virus

The HBx open reading frame exists only in HBV infecting mammals. A putative X protein was described for DHBV (Chang et al. 2001 ) Rating=0 , but has no apparent function in vitro or in vivo (Meier et al. 2003 ) Rating=2. The X protein would therefore be necessary only in mammals.

comments: Mammalian and particularly primate retroviruses encode for supplemental proteins compared to avian retroviruses. Most of them counteract host defenses which are stronger in mammals, presumably due to the evolution history which implies many endogenous retroviruses. HBV would be similar in the fact that the X would be necessary to circumvent mammals specific cellular defenses.

HBx Characterization

Murakami et al. 1994 (trans-repression region), Li et al. 2009 (DDB1-binding motif), Li et al. 2008 (mitochondrial targeting region), Diao et al. 2008(14-3-3 binding motif), Elmore et al. 1997 (P53 binding region), Tang et al. 2005(trans-activation regions)

Localization

HBx is primarily localized in the nucleus at low expression levels but accumulates in the cytoplasm at elevated HBx levels (Cha et al. 2009 ). HBx shuttles between the cytoplasm and the nucleus through a Crm-1-dependent nuclear export pathway (Forgues et al. 2001 ). HBx has been detected in the mitochondria as well (Li et al. 2008 ).



HBx turnover

HBx is expressed early in the replication cycle (Wu et al. 1991 ) Rating=2, (Doitsh et al. 2004 ) Rating=2. HBx can be ubiquitinated and degraded through the ubiquitin-proteasome pathway. It has been proposed that degradation of HBx is stimulated by HBV core protein (HBc) (Kim et al. 2003 ) Rating=1, by Hdj1 (Sohn et al. 2006 ) Rating=1. More recently, Siah, a novel E3 ubiquitin ligase for HBx, has been shown to interact with HBx and facilitates HBx poly-ubiquitylation and proteasomal degradation (Zaho et al. 2011 ) Rating=1. TSPX tumor suppressor has also been implicated in HBx degradation (Kido et al. 2011 ) Rating=1.



HBx and Hepatocellular Carcinomas

HBx transactivates viral (Zaho et al. 2011 ) and cellular genes expression either by interacting with various transcription factors, coactivators, and components of the basal transcription machinery in the nucleus or by activating signaling pathways in the cytoplasm (Ma et al. 2011 ) Rating=Review. These pathways seem to globally upregulate viral replication and cell survival/proliferation. As a consequence, HBx probably participates in inflammation/fibrosis processes and hepatocellular carcinoma (HCC) development (Brechot et al. 2010 ) Rating=Review. . The viral protein mostly integrated in the chromosomal DNA of patients with HCC is HBx (Paterlini et al. 1995 ) Rating=1.



This page has been funded in part by Hoffmann-La Roche