Inhibition of Hepatitis B virus replication by Phospholipid scramblase 1 in vitro and in vivo

Yang, Jing; Zhu, Xin; Liu, Juan; Ding, Xiaoran; Han, Min; Hu, Wei; Wang, Xuejun; Zhou, Zhe; Wang, Shengqi

doi:10.1016/j.antiviral.2012.01.010

Cited by 28 publications

(23 citation statements)

References 45 publications

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“…In addition, PLSCR1 contains a nuclear localization signal and a DNA-binding domain and is upregulated in response to cytokines and other inflammatory stimuli (Kodigepalli et al, 2015). Its name notwithstanding, PLSCR1 is unlikely to possess intrinsic scramblase activity (Segawa and Nagata, 2015) but has been implicated in calcium-dependent PtdSer externalization (Zhao et al, 1998), inositol 1,4,5-triphosphate receptor (IP3R) regulation (Zhou et al, 2005), and antiviral responses in vitro (Dong et al, 2004; Yang et al, 2012). We therefore sought to inhibit its activity in vivo.…”

Section: Resultsmentioning

confidence: 99%

Phosphatidylserine Exposure Controls Viral Innate Immune Responses by Microglia

Tufail

Cook

Fourgeaud

et al. 2017

Neuron

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SUMMARY Microglia are the intrinsic immune sentinels of the central nervous system. Their activation restricts tissue injury and pathogen spread, but in some settings, including viral infection, this response can contribute to cell death and disease. Identifying mechanisms that control microglial responses is therefore an important objective. Using replication-incompetent adenovirus 5 (Ad5)-based vectors as a model, we investigated the mechanisms through which microglia recognize and respond to viral uptake. Transgenic, immunohistochemical, molecular-genetic, and fluorescence imaging approaches revealed that phosphatidylserine (PtdSer) exposure on the outer leaflet of transduced cells triggers their engulfment by microglia through TAM receptor-dependent mechanisms. We show that inhibition of phospholipid scramblase 1 (PLSCR1) activity reduces intracellular calcium dysregulation, prevents PtdSer externalization, and enables months-long protection of vector-transduced, transgene-expressing cells from microglial phagocytosis. Our study identifies PLSCR1 as a potent target through which the innate immune response to viral vectors, and potentially other stimuli, may be controlled.

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Section: Resultsmentioning

confidence: 99%

Phosphatidylserine Exposure Controls Viral Innate Immune Responses by Microglia

Tufail

Cook

Fourgeaud

et al. 2017

Neuron

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“…It can also negatively regulate Tax-mediated transactivation of HTLV-1 LTR [ 18 ]. PLSCR1 suppresses hepatitis B and C viral replication which may be mediated through activation of the Jak/STAT signaling cascade [ 14 , 15 ]. Reduced expression of PLSCR1 can also lead to increased levels of vesicular stomatitis as well as encephalomyocarditis viruses [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…Phospholipid scramblase 1 (PLSCR1), located at 3q23, is a well-established target of IFN signaling and an important mediator of anti-viral functions of IFNs [ 14 – 19 ]. PLSCR1 is transcriptionally regulated by IFN via a signaling pathway involving activation of PKC-δ, JNK, and STAT1 [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Induction of PLSCR1 in a STING/IRF3-Dependent Manner upon Vector Transfection in Ovarian Epithelial Cells

Kodigepalli

Nanjundan

2015

PLoS ONE

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Toll-like receptors (TLRs) are the primary sensors of the innate immune system that recognize pathogenic nucleic acids including double-stranded plasmid DNA (dsDNA). TLR signaling activates multiple pathways including IRF3 which is involved in transcriptional induction of inflammatory cytokines (i.e. interferons (IFNs)). Phospholipid scramblase 1, PLSCR1, is a highly inducible IFN-regulated gene mediating anti-viral properties of IFNs. Herein, we report a novel finding that dsDNA transfection in T80 immortalized normal ovarian surface epithelial cell line leads to a marked increase in PLSCR1 mRNA and protein. We also noted a comparable response in primary mammary epithelial cells (HMECs). Similar to IFN-2α treated cells, de novo synthesized PLSCR1 was localized predominantly to the plasma membrane. dsDNA transfection, in T80 and HMEC cells, led to activation of MAPK and IRF3. Although inhibition of MAPK (using U0126) did not modulate PLSCR1 mRNA and protein, IRF3 knockdown (using siRNA) significantly ablated the PLSCR1 induction. In prior studies, the activation of IRF3 was shown to be mediated by cGAS-STING pathway. To investigate the contribution of STING to PLSCR1 induction, we utilized siRNA to reduce STING expression and observed that PLSCR1 protein was markedly reduced. In contrast to normal T80/HMECs, the phosphorylation of IRF3 as well as induction of STING and PLSCR1 were absent in ovarian cancer cells (serous, clear cell, and endometrioid) suggesting that the STING/IRF3 pathway may be dysregulated in these cancer cells. However, we also noted induction of different TLR and IFN mRNAs between the T80 and HEY (serous epithelial ovarian carcinoma) cell lines upon dsDNA transfection. Collectively, these results indicate that the STING/IRF3 pathway, activated following dsDNA transfection, contributes to upregulation of PLSCR1 in ovarian epithelial cells.

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“…Cells with reduced expression of PLSCR1 (via siRNA or fibroblasts from PLSCR1 −/− knockout mice) contained increased viral titers of vesicular stomatitis (VSV) and encephalomyocarditis (EMCV) viruses [96]. In HepG2 and Huh7 cell lines (as well as in mice), expression of PLSCR1 affects Hepatitis B virus (HBV) replication (reduction of viral proteins, RNAs, and DNA replicative intermediates) [97]. Although PLSCR1 was upregulated via IFN‐α and IFN‐γ to oppose hepatitis C virus (HCV) replication [98], PLSCR1 was also reported to promote viral entry of HCV [99].…”

Section: Expression Regulation and Localization Of Phospholipid Scrmentioning

confidence: 99%

Roles and regulation of phospholipid scramblases

et al. 2014

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Phospholipid scramblase activity is involved in the collapse of phospholipid (PL) asymmetry at the plasma membrane leading to externalization of phosphatidylserine. This activity is crucial for initiation of the blood coagulation cascade and for recognition/elimination of apoptotic cells by macrophages. Efforts to identify gene products associated with this activity led to the characterization of PL scramblase (PLSCR) and XKR family members which contribute to phosphatidylserine exposure in response to apoptotic stimuli. Meanwhile, TMEM16 family members were identified to externalize phosphatidylserine in response to elevated calcium in Scott syndrome platelets, which is critical for activation of the coagulation cascade. Herein, we report their mechanisms of gene regulation, molecular functions independent of their scrambling activity, and their potential roles in pathogenic conditions.

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Inhibition of Hepatitis B virus replication by Phospholipid scramblase 1 in vitro and in vivo

Cited by 28 publications

References 45 publications

Phosphatidylserine Exposure Controls Viral Innate Immune Responses by Microglia

Phosphatidylserine Exposure Controls Viral Innate Immune Responses by Microglia

Induction of PLSCR1 in a STING/IRF3-Dependent Manner upon Vector Transfection in Ovarian Epithelial Cells

Roles and regulation of phospholipid scramblases

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