scholarly journals TRIM24 facilitates antiviral immunity through mediating K63-linked TRAF3 ubiquitination

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Qingchen Zhu ◽  
Tao Yu ◽  
Shucheng Gan ◽  
Yan Wang ◽  
Yifei Pei ◽  
...  
Keyword(s):  
Virus Infection ◽  
Vesicular Stomatitis Virus ◽  
Rna Virus ◽  
Antiviral Immunity ◽  
Type I ◽  
Antiviral Signaling ◽  
Unknown Mechanism ◽  
Positive Regulator ◽  
Transcriptional Suppression ◽  
Vesicular Stomatitis

Ubiquitination is an essential mechanism in the control of antiviral immunity upon virus infection. Here, we identify a series of ubiquitination-modulating enzymes that are modulated by vesicular stomatitis virus (VSV). Notably, TRIM24 is down-regulated through direct transcriptional suppression induced by VSV-activated IRF3. Reducing or ablating TRIM24 compromises type I IFN (IFN-I) induction upon RNA virus infection and thus renders mice more sensitive to VSV infection. Mechanistically, VSV infection induces abundant TRIM24 translocation to mitochondria, where TRIM24 binds with TRAF3 and directly mediates K63-linked TRAF3 ubiquitination at K429/K436. This modification of TRAF3 enables its association with MAVS and TBK1, which consequently activates downstream antiviral signaling. Together, these findings establish TRIM24 as a critical positive regulator in controlling the activation of antiviral signaling and describe a previously unknown mechanism of TRIM24 function.

scholarly journals Vesicular stomatitis virus as a flexible platform for oncolytic virotherapy against cancer

2012 ◽  
Vol 93 (12) ◽  
pp. 2529-2545 ◽  
Author(s):  
Eric Hastie ◽  
Valery Z. Grdzelishvili
Keyword(s):  
Cancer Cells ◽  
Vesicular Stomatitis Virus ◽  
Reverse Genetics ◽  
Cell Transformation ◽  
Rna Virus ◽  
Type I ◽  
Delivery Methods ◽  
Recombinant Viruses ◽  
Antiviral Responses ◽  
Vesicular Stomatitis

Oncolytic virus (OV) therapy is an emerging anti-cancer approach that utilizes viruses to preferentially infect and kill cancer cells, while not harming healthy cells. Vesicular stomatitis virus (VSV) is a prototypic non-segmented, negative-strand RNA virus with inherent OV qualities. Antiviral responses induced by type I interferon pathways are believed to be impaired in most cancer cells, making them more susceptible to VSV than normal cells. Several other factors make VSV a promising OV candidate for clinical use, including its well-studied biology, a small, easily manipulated genome, relative independence of a receptor or cell cycle, cytoplasmic replication without risk of host-cell transformation, and lack of pre-existing immunity in humans. Moreover, various VSV-based recombinant viruses have been engineered via reverse genetics to improve oncoselectivity, safety, oncotoxicity and stimulation of tumour-specific immunity. Alternative delivery methods are also being studied to minimize premature immune clearance of VSV. OV treatment as a monotherapy is being explored, although many studies have employed VSV in combination with radiotherapy, chemotherapy or other OVs. Preclinical studies with various cancers have demonstrated that VSV is a promising OV; as a result, a human clinical trial using VSV is currently in progress.

scholarly journals TLR7 and TLR8 activate distinct pathways in monocytes during RNA virus infection

2019 ◽  
Vol 12 (605) ◽  
pp. eaaw1347 ◽  
Author(s):  
Marine de Marcken ◽  
Khushwant Dhaliwal ◽  
Ann Caroline Danielsen ◽  
Anne Sophie Gautron ◽  
Margarita Dominguez-Villar
Keyword(s):  
Virus Infection ◽  
Influenza A ◽  
Rna Virus ◽  
White Blood Cells ◽  
Type I ◽  
Human Monocytes ◽  
T Helper ◽  
Antiviral Responses ◽  
Vesicular Stomatitis ◽  
Sense And Respond

Human blood CD14+ monocytes are bone marrow–derived white blood cells that sense and respond to pathogens. Although innate immune activation by RNA viruses preferentially occurs through intracellular RIG-I–like receptors, other nucleic acid recognition receptors, such as Toll-like receptors (TLRs), play a role in finely programming the final outcome of virus infection. Here, we dissected how human monocytes respond to infection with either Coxsackie (CV), encephalomyocarditis (EMCV), influenza A (IAV), measles (MV), Sendai (SV), or vesicular stomatitis (VSV) virus. We found that in monocytes, type I interferon (IFN) and cytokine responses to infection were RNA virus specific and differentially involved TLR7 and TLR8, which sense single-stranded RNA. These TLRs activated distinct signaling cascades in monocytes, which correlated with differences in the production of cytokines involved in the polarization of CD4+ T helper cells. Furthermore, we found that TLR7 signaling specifically increased expression of the transcription factor FOSL1, which reduced IL-27 and TNFα production by monocytes. TLR7, but not TLR8, activation of monocytes also stimulated Ca2+ flux that prevented type I IFN responses. Our work demonstrates that in human monocytes, TLR7 and TLR8 triggered different signaling pathways that contribute to distinct phenotypes during RNA virus infection. In addition, we defined individual targets within these pathways that promoted specific T helper and antiviral responses.

scholarly journals HIPK2 is necessary for type I interferon–mediated antiviral immunity

2019 ◽  
Vol 12 (573) ◽  
pp. eaau4604 ◽  
Author(s):  
Lili Cao ◽  
Guang Yang ◽  
Shandian Gao ◽  
Chunxia Jing ◽  
Ruth R. Montgomery ◽  
...  
Keyword(s):  
Rna Virus ◽  
Antiviral Immunity ◽  
Type I ◽  
Wild Type ◽  
Interacting Protein ◽  
Precise Control ◽  
Antiviral Responses ◽  
Type I Ifns ◽  
Vesicular Stomatitis ◽  
Deficient Mice

Precise control of interferons (IFNs) is crucial to maintain immune homeostasis. Here, we demonstrated that homeodomain-interacting protein kinase 2 (HIPK2) was required for the production of type I IFNs in response to RNA virus infection. HIPK2 deficiency markedly impaired IFN production in macrophages after vesicular stomatitis virus (VSV) infection, and HIPK2-deficient mice were more susceptible to lethal VSV disease than were wild-type mice. After VSV infection, HIPK2 was cleaved by active caspases, which released a hyperactive, N-terminal fragment that translocated to the nucleus and further augmented antiviral responses. In part, HIPK2 interacted with ELF4 and promoted its phosphorylation at Ser369, which enabledIfn-b transcription. In addition, HIPK2 production was stimulated by type I IFNs to further enhance antiviral immunity. These data suggest that the kinase activity and nuclear localization of HIPK2 are essential for the production of type I IFNs.

scholarly journals USP18 positively regulates innate antiviral immunity by promoting K63-linked polyubiquitination of MAVS

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jinxiu Hou ◽  
Lulu Han ◽  
Ze Zhao ◽  
Huiqing Liu ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Sendai Virus ◽  
Rna Virus ◽  
Antiviral Immunity ◽  
Encephalomyocarditis Virus ◽  
Type I ◽  
Antiviral Signaling ◽  
Central Function ◽  
Adaptor Molecule ◽  
Innate Antiviral Immunity

AbstractActivation of MAVS, an adaptor molecule in Rig-I-like receptor (RLR) signaling, is indispensable for antiviral immunity, yet the molecular mechanisms modulating MAVS activation are not completely understood. Ubiquitination has a central function in regulating the activity of MAVS. Here, we demonstrate that a mitochondria-localized deubiquitinase USP18 specifically interacts with MAVS, promotes K63-linked polyubiquitination and subsequent aggregation of MAVS. USP18 upregulates the expression and production of type I interferon following infection with Sendai virus (SeV) or Encephalomyocarditis virus (EMCV). Mice with a deficiency of USP18 are more susceptible to RNA virus infection. USP18 functions as a scaffold protein to facilitate the re-localization of TRIM31 and enhances the interaction between TRIM31 and MAVS in mitochondria. Our results indicate that USP18 functions as a post-translational modulator of MAVS-mediated antiviral signaling.

scholarly journals N6-methyladenosine RNA modification suppresses antiviral innate sensing pathways via reshaping double-stranded RNA

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Weinan Qiu ◽  
Qingyang Zhang ◽  
Rui Zhang ◽  
Yangxu Lu ◽  
Xin Wang ◽  
...  
Keyword(s):  
Rna Virus ◽  
Negative Regulator ◽  
Rna Modification ◽  
Type I ◽  
Viral Immunity ◽  
Potential Therapeutic Target ◽  
Viral Dsrna ◽  
Double Stranded Rna ◽  
Genetic Ablation ◽  
Vesicular Stomatitis

AbstractDouble-stranded RNA (dsRNA) is a virus-encoded signature capable of triggering intracellular Rig-like receptors (RLR) to activate antiviral signaling, but whether intercellular dsRNA structural reshaping mediated by the N6-methyladenosine (m6A) modification modulates this process remains largely unknown. Here, we show that, in response to infection by the RNA virus Vesicular Stomatitis Virus (VSV), the m6A methyltransferase METTL3 translocates into the cytoplasm to increase m6A modification on virus-derived transcripts and decrease viral dsRNA formation, thereby reducing virus-sensing efficacy by RLRs such as RIG-I and MDA5 and dampening antiviral immune signaling. Meanwhile, the genetic ablation of METTL3 in monocyte or hepatocyte causes enhanced type I IFN expression and accelerates VSV clearance. Our findings thus implicate METTL3-mediated m6A RNA modification on viral RNAs as a negative regulator for innate sensing pathways of dsRNA, and also hint METTL3 as a potential therapeutic target for the modulation of anti-viral immunity.

scholarly journals Interferon Beta and Interferon Alpha 2a Differentially Protect Head and Neck Cancer Cells from Vesicular Stomatitis Virus-Induced Oncolysis

2015 ◽  
Vol 89 (15) ◽  
pp. 7944-7954 ◽  
Author(s):  
Marlena M. Westcott ◽  
Jingfang Liu ◽  
Karishma Rajani ◽  
Ralph D'Agostino ◽  
Douglas S. Lyles ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Vesicular Stomatitis Virus ◽  
Oncolytic Viruses ◽  
Type I ◽  
Normal Cells ◽  
Vesicular Stomatitis

ABSTRACTOncolytic viruses (OV) preferentially kill cancer cells due in part to defects in their antiviral responses upon exposure to type I interferons (IFNs). However, IFN responsiveness of some tumor cells confers resistance to OV treatment. The human type I IFNs include one IFN-β and multiple IFN-α subtypes that share the same receptor but are capable of differentially inducing biological responses. The role of individual IFN subtypes in promoting tumor cell resistance to OV is addressed here. Two human IFNs which have been produced for clinical use, IFN-α2a and IFN-β, were compared for activity in protecting human head and neck squamous cell carcinoma (HNSCC) lines from oncolysis by vesicular stomatitis virus (VSV). Susceptibility of HNSCC lines to killing by VSV varied. VSV infection induced increased production of IFN-β in resistant HNSCC cells. When added exogenously, IFN-β was significantly more effective at protecting HNSCC cells from VSV oncolysis than was IFN-α2a. In contrast, normal keratinocytes and endothelial cells were protected equivalently by both IFN subtypes. Differential responsiveness of tumor cells to IFN-α and -β was further supported by the finding that autocrine IFN-β but not IFN-α promoted survival of HNSCC cells during persistent VSV infection. Therefore, IFN-α and -β differentially affect VSV oncolysis, justifying the evaluation and comparison of IFN subtypes for use in combination with VSV therapy. Pairing VSV with IFN-α2a may enhance selectivity of oncolytic VSV therapy for HNSCC by inhibiting VSV replication in normal cells without a corresponding inhibition in cancer cells.IMPORTANCEThere has been a great deal of progress in the development of oncolytic viruses. However, a major problem is that individual cancers vary in their sensitivity to oncolytic viruses. In many cases this is due to differences in their production and response to interferons (IFNs). The experiments described here compared the responses of head and neck squamous cell carcinoma cell lines to two IFN subtypes, IFN-α2a and IFN-β, in protection from oncolytic vesicular stomatitis virus. We found that IFN-α2a was significantly less protective for cancer cells than was IFN-β, whereas normal cells were equivalently protected by both IFNs. These results suggest that from a therapeutic standpoint, selectivity for cancer versus normal cells may be enhanced by pairing VSV with IFN-α2a.

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