Hepatitis B virus (HBV) is a major risk factor for the development and progression of hepatocellular carcinoma (HCC). It has been reported that viral infection can interfere with cellular microRNA (miRNA) expression and participate in the pathogenesis of oncogenicity. Here, we report that decreasing levels of the expression of the miRNA miR-192-3p is associated with rising levels of HBV DNA in the serum of HBV patients. We revealed that HBV infection repressed the expression of miR-192-3p through HBx interaction with c-Myc. We further showed that miR-192-3p was repressed by HBV transfection in vitro and in mouse model, leading to cellular autophagy. Using an miRNA target prediction database miRBase, we identified XIAP as a novel target gene of miR-192-3p and demonstrated that miR-192-3p directly targeted XIAP 3'-untranslated region (3'-UTR) of XIAP mRNA. Importantly, we discovered that HBV promoted autophagy through miR-192-3p-XIAP axis and that this process was important for HBV replication in vitro and in vivo. We demonstrated that miR-192-3p functioned through the NF-κB signaling pathway to inhibit autophagy, thereby reducing HBV replication. Our findings indicate that miR-192-3p is a novel regulator of HBV infection and may play a potential role in HCC. It may also serve as a new biomarker or therapeutic target for HBV patients. This article is protected by copyright. All rights reserved.
MAVS and MITA are essential adaptor proteins mediating innate antiviral immune responses against RNA and DNA viruses, respectively. Here we show that RNF115 plays dual roles in response to RNA or DNA virus infections by catalyzing distinct types of ubiquitination of MAVS and MITA at different phases of viral infection. RNF115 constitutively interacts with and induces K48-linked ubiquitination and proteasomal degradation of homeostatic MAVS in uninfected cells, whereas associates with and catalyzes K63-linked ubiquitination of MITA after HSV-1 infection. Consistently, the protein levels of MAVS are substantially increased in Rnf115−/− organs or cells without viral infection, and HSV-1-induced aggregation of MITA is impaired in Rnf115−/− cells compared to the wild-type counterparts. Consequently, the Rnf115−/− mice exhibit hypo- and hyper-sensitivity to EMCV and HSV-1 infection, respectively. These findings highlight dual regulation of cellular antiviral responses by RNF115-mediated ubiquitination of MAVS and MITA and contribute to our understanding of innate immune signaling.
BackgroundHepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and infection with hepatitis B virus (HBV) is a leading cause of HCC. Previous studies have demonstrated that expression of the tumor inhibitor miR-340 is significantly downregulated in HCC tissues compared with normal liver tissues. However, the precise biological role of miR-340-5p in HBV–HCC and its molecular mechanism of action remain unknown.ResultsExpression of miR-340-5p was downregulated in HBV-associated HCC liver tissue and HBV-infected cells, facilitating migration of liver cancer cells. Signal transducer and activator of transcription (STAT)3 was found to be a direct functional target of miR-340-5p. The regulation of STAT3 expression by miR-340-5p was assessed using qRT-PCR and western blotting, and the effects of exogenous miR-340-5p and STAT3 on the migration of HBV-infected cells were evaluated in vitro using Transwell® and wound-healing assays. The expression of E-cadherin and vimentin, associated with epithelial–mesenchymal transition, was also assessed using Western blotting after transfection of miR-340-5p mimics and/or STAT3 expression vectors. Overexpression of STAT3 resulted in rescue of HBV effects, decreased E-cadherin expression, increased vimentin expression, and ultimately, enhanced cell migration. Re-introduction of the STAT3 CDS led to marked reversal of the inhibition of cell migration in HBV-infected cells mediated by miR-340-5p.ConclusionsHepatitis B virus promotes the migration of liver cancer cells by downregulating miR-340-5p expression to induce STAT3 overexpression. Our results show that STAT3 plays a key role in regulating cell migration in HBV–HCC involving miR-340-5p.
Hepatocellular carcinoma ( HCC ) is a common cancer with poor prognosis. Hepatitis B virus ( HBV ) is one of the leading causes of HCC , but the precise mechanisms by which this infection promotes cancer development are not fully understood. Recently, miR‐340‐5p, a micro RNA (mi RNA ) that has been identified as a cancer suppressor gene, was found to inhibit the migration and invasion of liver cancer cells. However, the effect of miR‐340‐5p on cell proliferation and apoptosis in HBV ‐associated HCC remains unknown. In our study, we show that miR‐340‐5p plays an important role during HBV infection and hepatocellular carcinoma development. Specifically, this mi RNA directly binds to the mRNA encoding activating transcription factor 7 ( ATF 7), a protein that both promotes cell proliferation and suppresses apoptosis through its interaction with heat shock protein A member 1B ( HSPA 1B). We further found that miR‐340‐5p is downregulated by HBV , which enhances ATF 7 expression, leading to enhanced cell proliferation and inhibition of apoptosis. Notably, ATF 7 is upregulated in HCC tissue, suggesting that HBV may target miR‐340‐5p in vivo to promote ATF 7/ HSPA 1B‐mediated proliferation and apoptosis and regulate liver cancer progression. This work helps to elucidate the complex interactions between HBV and host mi RNA s and further suggests that miR‐340‐5p may represent a promising candidate for the development of improved therapeutic strategies for HCC .
The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) plays a critical role in antiviral immunity and autoimmunity. The activity and stability of cGAS are fine-tuned by post-translational modifications. Here, we show that ariadne RBR E3 ubiquitin protein ligase 1 (ARIH1) catalyzes the mono-ISGylation and induces the oligomerization of cGAS, thereby promoting antiviral immunity and autoimmunity. Knockdown or knockout of ARIH1 significantly inhibits herpes simplex virus 1 (HSV-1)- or cytoplasmic DNA-induced expression of type I interferons (IFNs) and proinflammatory cytokines. Consistently, tamoxifen-treated ER-Cre;Arih1fl/fl mice and Lyz2-Cre; Arih1fl/fl mice are hypersensitive to HSV-1 infection compared with the controls. In addition, deletion of ARIH1 in myeloid cells alleviates the autoimmune phenotypes and completely rescues the autoimmune lethality caused by TREX1 deficiency. Mechanistically, HSV-1- or cytosolic DNA-induced oligomerization and activation of cGAS are potentiated by ISGylation at its K187 residue, which is catalyzed by ARIH1. Our findings thus reveal an important role of ARIH1 in innate antiviral and autoimmune responses and provide insight into the post-translational regulation of cGAS.
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