scholarly journals Contributions of Ubiquitin and Ubiquitination to Flaviviral Antagonism of Type I IFN

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 763
Author(s):  
Erika Hay-McCullough ◽  
Juliet Morrison
Keyword(s):  
Immune Response ◽  
Host Response ◽  
Type I Interferon ◽  
Antiviral Response ◽  
Cellular Protein ◽  
Type I ◽  
Type I Ifn ◽  
Cellular Regulation ◽  
Host Antiviral Response

Flaviviruses implement a broad range of antagonism strategies against the host antiviral response. A pivotal component of the early host response is production and signaling of type I interferon (IFN-I). Ubiquitin, a prevalent cellular protein-modifying molecule, is heavily involved in the cellular regulation of this and other immune response pathways. Viruses use ubiquitin and ubiquitin machinery to antagonize various steps of these pathways through diverse mechanisms. Here, we highlight ways in which flaviviruses use or inhibit ubiquitin to antagonize the antiviral IFN-I response.

scholarly journals miR-26a Inhibits Feline Herpesvirus 1 Replication by Targeting SOCS5 and Promoting Type I Interferon Signaling

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 2 ◽  
Author(s):  
Jikai Zhang ◽  
Zhijie Li ◽  
Jiapei Huang ◽  
Hang Yin ◽  
Jin Tian ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Infection ◽  
Innate Immune Response ◽  
Antiviral Response ◽  
Innate Immune ◽  
Host Cells ◽  
Type I ◽  
Type I Ifn ◽  
Feline Herpesvirus ◽  
Herpesvirus 1

In response to viral infection, host cells activate various antiviral responses to inhibit virus replication. While feline herpesvirus 1 (FHV-1) manipulates the host early innate immune response in many different ways, the host could activate the antiviral response to counteract it through some unknown mechanisms. MicroRNAs (miRNAs) which serve as a class of regulatory factors in the host, participate in the regulation of the host innate immune response against virus infection. In this study, we found that the expression levels of miR-26a were significantly upregulated upon FHV-1 infection. Furthermore, FHV-1 infection induced the expression of miR-26a via a cGAS-dependent pathway, and knockdown of cellular cGAS significantly blocked the expression of miR-26a induced by poly (dA:dT) or FHV-1 infection. Next, we investigated the biological function of miR-26a during viral infection. miR-26a was able to increase the phosphorylation of STAT1 and promote type I IFN signaling, thus inhibiting viral replication. The mechanism study showed that miR-26a directly targeted host SOCS5. Knockdown of SOCS5 increased the phosphorylation of STAT1 and enhanced the type I IFN-mediated antiviral response, and overexpression of suppressor of the cytokine signalling 5 (SOCS5) decreased the phosphorylation of STAT1 and inhibited the type I IFN-mediated antiviral response. Meanwhile, with the knockdown of SOCS5, the upregulated expression of phosphorylated STAT1 and the anti-virus effect induced by miR-26a were significantly inhibited. Taken together, our data demonstrated a new strategy of host miRNAs against FHV-1 infection by enhancing IFN antiviral signaling.

scholarly journals ELF4 is critical for induction of type I interferon and the host antiviral response

2013 ◽  
Vol 14 (12) ◽  
pp. 1237-1246 ◽  
Author(s):  
Fuping You ◽  
Penghua Wang ◽  
Long Yang ◽  
Guang Yang ◽  
Yang O Zhao ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Antiviral Response ◽  
Type I ◽  
Host Antiviral Response

scholarly journals LncRNAs in the Type I Interferon Antiviral Response

2020 ◽  
Vol 21 (17) ◽  
pp. 6447 ◽  
Author(s):  
Beatriz Suarez ◽  
Laura Prats-Mari ◽  
Juan P. Unfried ◽  
Puri Fortes
Keyword(s):  
Immune Response ◽  
Type I Interferon ◽  
Cancer Control ◽  
Antiviral Response ◽  
Type I ◽  
Antiviral Immune Response ◽  
Cell Type Specific ◽  
Non Coding Rnas ◽  
Coding Capacity ◽  
Proinflammatory Factors

The proper functioning of the immune system requires a robust control over a delicate equilibrium between an ineffective response and immune overactivation. Poor responses to viral insults may lead to chronic or overwhelming infection, whereas unrestrained activation can cause autoimmune diseases and cancer. Control over the magnitude and duration of the antiviral immune response is exerted by a finely tuned positive or negative regulation at the DNA, RNA, and protein level of members of the type I interferon (IFN) signaling pathways and on the expression and activity of antiviral and proinflammatory factors. As summarized in this review, committed research during the last decade has shown that several of these processes are exquisitely regulated by long non-coding RNAs (lncRNAs), transcripts with poor coding capacity, but highly versatile functions. After infection, viruses, and the antiviral response they trigger, deregulate the expression of a subset of specific lncRNAs that function to promote or repress viral replication by inactivating or potentiating the antiviral response, respectively. These IFN-related lncRNAs are also highly tissue- and cell-type-specific, rendering them as promising biomarkers or therapeutic candidates to modulate specific stages of the antiviral immune response with fewer adverse effects.

scholarly journals Blocking Type I Interferon Signaling Rescues Lymphocytes from Oxidative Stress, Exhaustion, and Apoptosis in a Streptozotocin-Induced Mouse Model of Type I Diabetes

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Hany M. Ibrahim ◽  
Ibrahim A. El-Elaimy ◽  
Heba M. Saad Eldien ◽  
Badr Mohamed Badr ◽  
Danny M. Rabah ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Proinflammatory Cytokines ◽  
Type I Interferon ◽  
Type I ◽  
Diabetic Mice ◽  
Type I Ifn ◽  
Proliferative Capacity ◽  
Blocking Type

Elevated levels of type I interferon (IFN) during type 1 diabetes mellitus (T1D) are associated with a defective immune response. In the present study, we investigated whether blocking type I IFN signaling during streptozotocin- (STZ-) induced T1D in mice improves lymphocyte proliferation and escape from continuous apoptosis. Three groups of mice were examined: diabetic mice, type I IFN signaling-incompetent diabetic mice, and control nondiabetic mice. We first found that diabetes induction was accompanied by an elevation in the plasma levels of reactive oxygen species (ROS), hydroperoxide, malondialdehyde (MDN), and the proinflammatory cytokines IL-1α, IL-1β, IL-6, and CXCL10. Blocking type 1 IFN signaling in diabetic mice significantly decreased the levels of oxidative stress and proinflammatory cytokines. In addition, lymphocytes from diabetic mice exhibited a marked reduction in their proliferative capacity, increased apoptosis, upregulation of the exhaustion marker PD-1, and aberrant phosphorylation of STAT1, STAT2, AKT and IκB-α. Interestingly, following the blocking of type I IFN signaling in diabetic mice, the lymphocytes exhibited restored proliferative capacity, decreased apoptosis, normal expression of PD-1, and normal phosphorylation of STAT1, STAT2, AKT and IκB-α. Our data suggest that elevated levels of type I IFN during T1D trigger lymphocyte exhaustion and a defective lymphocyte-medicated immune response.

scholarly journals Emerging Alphaviruses Are Sensitive to Cellular States Induced by a Novel Small-Molecule Agonist of the STING Pathway

2017 ◽  
Vol 92 (6) ◽  
Author(s):  
Bryan Gall ◽  
Kara Pryke ◽  
Jinu Abraham ◽  
Nobuyo Mizuno ◽  
Sara Botto ◽  
...  
Keyword(s):  
Immune Response ◽  
Type I Interferon ◽  
Adaptor Protein ◽  
Human Cells ◽  
Innate Immune ◽  
Therapeutic Drug ◽  
Type I ◽  
Type I Ifn ◽  
Virus Growth

ABSTRACT The type I interferon (IFN) system represents an essential innate immune response that renders cells resistant to virus growth via the molecular actions of IFN-induced effector proteins. IFN-mediated cellular states inhibit growth of numerous and diverse virus types, including those of known pathogenicity as well as potentially emerging agents. As such, targeted pharmacologic activation of the IFN response may represent a novel therapeutic strategy to prevent infection or spread of clinically impactful viruses. In light of this, we employed a high-throughput screen to identify small molecules capable of permeating the cell and of activating IFN-dependent signaling processes. Here we report the identification and characterization of N -(methylcarbamoyl)-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]sulfanyl}-2-phenylacetamide (referred to as C11), a novel compound capable of inducing IFN secretion from human cells. Using reverse genetics-based loss-of-function assays, we show that C11 activates the type I IFN response in a manner that requires the adaptor protein STING but not the alternative adaptors MAVS and TRIF. Importantly, treatment of cells with C11 generated a cellular state that potently blocked replication of multiple emerging alphavirus types, including chikungunya, Ross River, Venezuelan equine encephalitis, Mayaro, and O'nyong-nyong viruses. The antiviral effects of C11 were subsequently abrogated in cells lacking STING or the type I IFN receptor, indicating that they are mediated, at least predominantly, by way of STING-mediated IFN secretion and subsequent autocrine/paracrine signaling. This work also allowed characterization of differential antiviral roles of innate immune signaling adaptors and IFN-mediated responses and identified MAVS as being crucial to cellular resistance to alphavirus infection. IMPORTANCE Due to the increase in emerging arthropod-borne viruses, such as chikungunya virus, that lack FDA-approved therapeutics and vaccines, it is important to better understand the signaling pathways that lead to clearance of virus. Here we show that C11 treatment makes human cells refractory to replication of a number of these viruses, which supports its value in increasing our understanding of the immune response and viral pathogenesis required to establish host infection. We also show that C11 depends on signaling through STING to produce antiviral type I interferon, which further supports its potential as a therapeutic drug or research tool.

scholarly journals Retinoid X receptor α attenuates host antiviral response by suppressing type I interferon

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Feng Ma ◽  
Su-Yang Liu ◽  
Bahram Razani ◽  
Neda Arora ◽  
Bing Li ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Antiviral Response ◽  
Retinoid X Receptor ◽  
Type I ◽  
Host Antiviral Response

scholarly journals Arenaviral Nucleoproteins Suppress PACT-Induced Augmentation of RIG-I Function To Inhibit Type I Interferon Production

2018 ◽  
Vol 92 (13) ◽  
pp. e00482-18 ◽  
Author(s):  
Junjie Shao ◽  
Qinfeng Huang ◽  
Xiaoying Liu ◽  
Da Di ◽  
Yuying Liang ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Hemorrhagic Fever ◽  
Cellular Protein ◽  
Rnase Activity ◽  
Block Type ◽  
Type I ◽  
Type I Ifn ◽  
Viral Pathogen ◽  
Virus Growth ◽  
Type I Ifns

ABSTRACT RIG-I is a major cytoplasmic sensor of viral pathogen-associated molecular pattern (PAMP) RNA and induces type I interferon (IFN) production upon viral infection. A double-stranded RNA (dsRNA)-binding protein, PACT, plays an important role in potentiating RIG-I function. We have shown previously that arenaviral nucleoproteins (NPs) suppress type I IFN production via their RNase activity to degrade PAMP RNA. We report here that NPs of arenaviruses block the PACT-induced enhancement of RIG-I function to mediate type I IFN production and that this inhibition is dependent on the RNase function of NPs, which is different from that of a known mechanism of other viral proteins to abolish the interaction between PACT and RIG-I. To understand the biological roles of PACT and RIG-I in authentic arenavirus infection, we analyze growth kinetics of recombinant Pichinde virus (PICV), a prototypical arenavirus, in RIG-I knockout (KO) and PACT KO mouse embryonic fibroblast (MEF) cells. Wild-type (WT) PICV grew at higher titers in both KO MEF lines than in normal MEFs, suggesting the important roles of these cellular proteins in restricting virus replication. PICV carrying the NP RNase catalytically inactive mutation could not grow in normal MEFs but could replicate to some extent in both KO MEF lines. The level of virus growth was inversely correlated with the amount of type I IFNs produced. These results suggest that PACT plays an important role in potentiating RIG-I function to produce type I IFNs in order to restrict arenavirus replication and that viral NP RNase activity is essential for optimal viral replication by suppressing PACT-induced RIG-I activation. IMPORTANCE We report here a new role of the nucleoproteins of arenaviruses that can block type I IFN production via their specific inhibition of the cellular protein sensors of virus infection (RIG-I and PACT). Our results suggest that PACT plays an important role in potentiating RIG-I function to produce type I IFNs in order to restrict arenavirus replication. This new knowledge can be exploited for the development of novel antiviral treatments and/or vaccines against some arenaviruses that can cause severe and lethal hemorrhagic fever diseases in humans.

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