Interactome Map Reveals Phospholipid Scramblase 1 as a Novel Regulator of Hepatitis B Virus X Protein

Abstract

HBV X protein plays crucial roles during viral infection and hepatocellular carcinoma (HCC) development through interaction with various host factors. Here, we mapped the interactome of HBx using a yeast two-hybrid screen. Nine human proteins were identified as novel interacting partners of HBx, one of which is phospholipid scramblase 1 (PLSCR1). PLSCR1 is an interferon-inducible protein that mediates antiviral activity against DNA and RNA viruses. However, the molecular mechanisms of PLSCR1 activity against HBV remain unclear. Here, we reported that PLSCR1 promotes HBx degradation by a proteasome- and ubiquitin-dependent mechanism. Furthermore, we found that PLSCR1 inhibits HBx-mediated cell proliferation. After HBV infection, the protein level of PLSCR1 in plasma is elevated, and chronic hepatitis B patients with low plasma levels of PLSCR1 have a high risk of developing HCC. These results suggest that the nuclear trafficking of PLSCR1 mediates the antiviral activity and anticarcinogenesis against HBV by regulating HBx stability.

RNA interference‑mediated downregulation of phospholipid scramblase 1 expression in primary liver cancer <em>in&nbsp;vitro</em>

“…The present study also demonstrated that the expression of PLSCR1 in primary liver cancer was associated with the HBs-Ag status. Yuan et al ( 24 ) reported an important role for PLSCR1 in the host defence against HBV infection and the development of primary liver cancer in patients with HBV, which are consistent with the findings of the present study.…”

Proteomic Analysis of the Secretome of Porcine Alveolar Macrophages Infected with Porcine Reproductive and Respiratory Syndrome Virus

“…Among the 95 differentially expressed proteins, 16 were involved in the regulation of the host immune response (Table ). For example, IRF3, which is a key regulator of the type I IFN pathway, and phospholipid scramblase 1 (PLSCR1), which is an IFN‐inducible protein that mediates antiviral activities against DNA and RNA viruses, were expressed at significantly higher levels in PRRSV‐infected cell supernatants than mock‐infected cell supernatants. Meanwhile, the expression levels of proteins involved in the antigen processing and presentation pathways, such as MHC class II antigen, dynactin, and antigen peptide transporter 2 (TAP2), were altered by PRRSV infection.…”

“…The up‐regulated proteins in the supernatant of PRRSV‐infected PAMs were enriched mainly in the KEGG terms of the TLR signaling pathway, RIG‐I‐like receptor signaling pathway, and NF‐kappa B signaling pathway, suggesting that these secreted proteins might be involved in regulation of these signaling pathways during PRRSV infection. For example, some IFN‐stimulated proteins, such as PLSCR1, which mediates antiviral activity against DNA and RNA viruses, and IRF3, which is a key regulator of the type I IFN pathway, showed significantly higher expression levels in PRRSV‐infected cell supernatants than in mock‐infected cell supernatants. However, PRRSV has evolved various mechanisms to antagonize the type I IFN response.…”

Phosphatidylserine Exposure Controls Viral Innate Immune Responses by Microglia

“…This approach therefore holds promise for constructing Ad-based vectors with reduced inflammatory responses and cell loss, potentially allowing prolonged expression of therapeutic genes in preclinical and clinical gene therapy trials (Castro et al, 2014; Soria et al, 2010; Tobias et al, 2013; Wold and Toth, 2013). In vitro studies indicate that PLSCR1 may also play important roles in the antiviral response to other viruses, including herpes simplex virus (Talukder et al, 2012), vesicular stomatitis virus (Dong et al, 2004), and hepatitis B and C viruses (Metz et al, 2012; Yuan et al, 2015). Beyond virus infection, PLSCR1 may be of importance in bacterial infection (Goth and Stephens, 2001; Lu et al, 2007), autoimmune disease (Amengual et al, 2013; Bernales et al, 2008; Suzuki et al, 2010), or cancer development (Fan et al, 2012; Kodigepalli et al, 2013; Kuo et al, 2011).…”