Abstract
Promyelocytic leukemia nuclear bodies (PML-NB) are sub-nuclear organelles that are the hub of numerous proteins. DNA/RNA viruses often hijack the cellular factors resident in PML-NBs to promote their proliferation in host cells. Hepatitis B virus (HBV), belonging to Hepadnaviridae family, remains undetected in early infection as it does not induce the innate immune response and is known to be the cause of several hepatic diseases leading to cirrhosis and hepatocellular carcinoma. The association of PML-NB proteins and HBV is being addressed in a number of recent studies. Here, we report that the PML-NB protein Speckled 110 kDa (Sp110) is SUMO1-modified and undergoes a deSUMOylation-driven release from the PML-NB in the presence of HBV. Intriguingly, Sp110 knockdown significantly reduced viral DNA load in the culture supernatant by activation of the type I interferon-response pathway. Furthermore, we found that Sp110 differentially regulates several direct target genes of hepatitis B virus protein X (HBx), a viral co-factor. Subsequently, we identified Sp110 as a novel interactor of HBx and found this association to be essential for the exit of Sp110 from the PML-NB during HBV infection and HBx recruitment on the promoter of these genes. HBx, in turn, modulates the recruitment of its associated transcription cofactors p300/HDAC1 to these co-regulated genes, thereby altering the host gene expression program in favor of viral persistence. Thus, we report a mechanism by which HBV can evade host immune response by hijacking the PML-NB protein Sp110, and therefore, we propose it to be a novel target for antiviral therapy.
Highlights
Promyelocytic leukemia nuclear bodies (PML-NB) are subnuclear organelles that are the hub of numerous proteins
Several DNA and RNA viruses have been reported to exploit resident factors of PML bodies, which occur by mainly two distinct mechanisms: (i) some of the viral proteins associate with PML body proteins leading to disruption of the sub-nuclear compartment, and (ii) the viral genome of few DNA viruses can associate with the PML nuclear body, which might contribute toward viral proliferation [5]
Hepatitis B virus, a Hepadnaviridae family virus, is the cause of many chronic hepatic diseases leading to cirrhosis and hepatocellular carcinoma, but the association of HBV and the PML-NBs are not much explored
Summary
Host transcription factor Speckled 110 kDa (Sp110), a nuclear body protein, is hijacked by hepatitis B virus protein X for viral persistence. Promyelocytic leukemia (PML) bodies are nuclear sub-structures, which are constituted of ϳ80 proteins including PML, Speckled 100-kDa protein (Sp100), transcription factor p53, the histone acetylase and co-activator CBP, the tumor suppressor Rb, the Bloom syndrome helicase BLM, heterochromatin protein 1 (HP1), etc As these proteins play a significant role in many crucial cellular pathways, PML-NBs are often targeted by the viral proteins [5]. We show that Sp110 remains in SUMO-1-modified form and undergoes a deSUMOylation-driven exit from the nuclear bodies in the presence of HBV or the HBV-encoded co-factor HBx. Sp110 was found to deregulate the expression of a large number of host genes, and interestingly, a significant number of them were direct targets of HBx, which were mostly implicated in the transcription, replication, repair, and immune-response pathways. Our study shows that the host protein Sp110 is one of the prime factors that is exploited by HBV and is crucial for the pathogenesis as its knockdown led to a dramatic viral elimination and is a potential therapeutic target
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