scholarly journals TRIMming Type I Interferon-Mediated Innate Immune Response in Antiviral and Antitumor Defense

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 279
Author(s):  
Ling Wang ◽  
Shunbin Ning
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Stress Responses ◽  
Viral Infections ◽  
Immune Escape ◽  
E3 Ligase ◽  
Innate Immune ◽  
Type I ◽  
Antiviral Immune Response ◽  
Wide Range

The tripartite motif (TRIM) family comprises at least 80 members in humans, with most having ubiquitin or SUMO E3 ligase activity conferred by their N-terminal RING domain. TRIMs regulate a wide range of processes in ubiquitination- or sumoylation-dependent manners in most cases, and fewer as adaptors. Their roles in the regulation of viral infections, autophagy, cell cycle progression, DNA damage and other stress responses, and carcinogenesis are being increasingly appreciated, and their E3 ligase activities are attractive targets for developing specific immunotherapeutic strategies for immune diseases and cancers. Given their importance in antiviral immune response, viruses have evolved sophisticated immune escape strategies to subvert TRIM-mediated mechanisms. In this review, we focus on their regulation of IFN-I-mediated innate immune response, which plays key roles in antiviral and antitumor defense.

scholarly journals PATTERN-RECOGNIZING RECEPTORS AND THE INNATE IMMUNE RESPONSE TO VIRAL INFECTION

2018 ◽  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Viral Infection ◽  
Innate Immune Response ◽  
English Literature ◽  
Innate Immune ◽  
Viral Pathogens ◽  
Antiviral Immune Response ◽  
Viral Antigens ◽  
Wide Range

The innate immune response to viral pathogens is crucial in mobilizing defensive reactions of an organism during the development of an acute viral infection. Cells of the innate immunity system detect viral antigens due to genetically programmed pattern-recognition receptors (PRRs), which are located either on the cell surface or inside the certain intracellular components. These image-recognizing receptors include Toll-like receptors (TLRs), retinoic acid-inducible gene I-like receptors (RIG-I-like receptors), nucleotide oligomerization domain-like receptors (NOD-like receptors), also known as NACHT, LRR and PYD domains of the protein, and cytosolic DNA sensors. The trigger mechanisms for these receptors are viral proteins, and nucleic acids serve as activators. The presence of PRRs that are responsible for the determination of viral antigens in cellular components allows the cells of innate immunity to recognize a wide range of viral agents that replicate in various cellular structures, and develop an immune response to them. This article summarizes the disparate data presented in modern English literature on the role of PRRs and the associated signaling pathways. Understanding the recognition of viral pathogens required triggering a cascade of cytokine and interferon production provides insights into how viruses activate the signal paths of PRRs and the effect of the interaction of viral antigens and these receptors on the formation of the antiviral immune response.

scholarly journals Bromodomain protein Brd3 promotes Ifnb1 transcription via enhancing IRF3/p300 complex formation and recruitment to Ifnb1 promoter in macrophages

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Wenhui Ren ◽  
Chunmei Wang ◽  
Qinlan Wang ◽  
Dezhi Zhao ◽  
Kai Zhao ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Innate Immune Response ◽  
Transcriptional Activation ◽  
Cell Cycle Progression ◽  
Innate Immune ◽  
Type I ◽  
Wide Range ◽  
Bromodomain Proteins ◽  
Protein Scaffolding

AbstractAs members of bromodomain and extra-terminal motif protein family, bromodomain-containing proteins regulate a wide range of biological processes including protein scaffolding, mitosis, cell cycle progression and transcriptional regulation. The function of these bromodomain proteins (Brds) in innate immune response has been reported but the role of Brd3 remains unclear. Here we find that virus infection significantly downregulate Brd3 expression in macrophages and Brd3 knockout inhibits virus-triggered IFN-β production. Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection. Importantly, Brd3 promotes the recruitment of IRF3/p300 complex to the promoter of Ifnb1, and increases the acetylation of histone3/histone4 within the Ifnb1 promoter, leading to the enhancement of type I interferon production. Therefore, our work indicated that Brd3 may act as a coactivator in IRF3/p300 transcriptional activation of Ifnb1 and provided new epigenetic mechanistic insight into the efficient activation of the innate immune response.

scholarly journals RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response

2021 ◽  
Vol 17 (3) ◽  
pp. e1009401
Author(s):  
Chenhui Li ◽  
Lele Zhang ◽  
Dong Qian ◽  
Mingxing Cheng ◽  
Haiyang Hu ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
E3 Ligase ◽  
Vital Role ◽  
Innate Immune ◽  
Type I ◽  
Pathway Activation ◽  
Sting Pathway ◽  
Signaling Activation

The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) has emerged as a fundamental component fueling the anti-pathogen immunity. Because of its pivotal role in initiating innate immune response, the activity of cGAS must be tightly fine-tuned to maintain immune homeostasis in antiviral response. Here, we reported that neddylation modification was indispensable for appropriate cGAS-STING signaling activation. Blocking neddylation pathway using neddylation inhibitor MLN4924 substantially impaired the induction of type I interferon and proinflammatory cytokines, which was selectively dependent on Nedd8 E2 enzyme Ube2m. We further found that deficiency of the Nedd8 E3 ligase Rnf111 greatly attenuated DNA-triggered cGAS activation while not affecting cGAMP induced activation of STING, demonstrating that Rnf111 was the Nedd8 E3 ligase of cGAS. By performing mass spectrometry, we identified Lys231 and Lys421 as essential neddylation sites in human cGAS. Mechanistically, Rnf111 interacted with and polyneddylated cGAS, which in turn promoted its dimerization and enhanced the DNA-binding ability, leading to proper cGAS-STING pathway activation. In the same line, the Ube2m or Rnf111 deficiency mice exhibited severe defects in innate immune response and were susceptible to HSV-1 infection. Collectively, our study uncovered a vital role of the Ube2m-Rnf111 neddylation axis in promoting the activity of the cGAS-STING pathway and highlighted the importance of neddylation modification in antiviral defense.

scholarly journals Fas-Associated Factor 1 Negatively Regulates the Antiviral Immune Response by Inhibiting Translocation of Interferon Regulatory Factor 3 to the Nucleus

2016 ◽  
Vol 36 (7) ◽  
pp. 1136-1151 ◽  
Author(s):  
Soonhwa Song ◽  
Jae-Jin Lee ◽  
Hee-Jung Kim ◽  
Jeong Yoon Lee ◽  
Jun Chang ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Antiviral Response ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Antiviral Immune Response ◽  
Associated Factor

This study is designed to examine the cellular functions of human Fas-associated factor 1 (FAF1) containing multiple ubiquitin-related domains. Microarray analyses revealed that interferon-stimulated genes related to the antiviral response are significantly increased in FAF1-knockdown HeLa cells. Silencing FAF1 enhanced the poly(I·C)- and respiratory syncytial virus (RSV)-induced production of type I interferons (IFNs), the target genes of interferon regulator factor 3 (IRF3). IRF3 is a key transcription factor in IFN-β signaling responsible for the host innate immune response. This study also found that FAF1 and IRF3 physically associate with IPO5/importin-β3 and that overexpression of FAF1 reduces the interaction between IRF3 and IPO5/importin-β3. These findings suggest that FAF1 negatively regulates IRF3-mediated IFN-β production and the antiviral innate immune response by regulating nuclear translocation of IRF3. We conclude that FAF1 plays a novel role in negatively regulating virus-induced IFN-β production and the antiviral response by inhibiting the translocation of active, phosphorylated IRF3 from the cytosol to the nucleus.

scholarly journals Subversion of Host Innate Immunity by Human Papillomavirus Oncoproteins

Pathogens ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 292 ◽  
Author(s):  
Irene Lo Cigno ◽  
Federica Calati ◽  
Silvia Albertini ◽  
Marisa Gariglio
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Human Papillomavirus ◽  
Signaling Pathways ◽  
Innate Immune Response ◽  
Immune Escape ◽  
Innate Immune ◽  
Transformed Cells ◽  
Type I ◽  
E6 And E7

The growth of human papillomavirus (HPV)-transformed cells depends on the ability of the viral oncoproteins E6 and E7, especially those from high-risk HPV16/18, to manipulate the signaling pathways involved in cell proliferation, cell death, and innate immunity. Emerging evidence indicates that E6/E7 inhibition reactivates the host innate immune response, reversing what until then was an unresponsive cellular state suitable for viral persistence and tumorigenesis. Given that the disruption of distinct mechanisms of immune evasion is an attractive strategy for cancer therapy, the race is on to gain a better understanding of E6/E7-induced immune escape and cancer progression. Here, we review recent literature on the interplay between E6/E7 and the innate immune signaling pathways cGAS/STING/TBK1, RIG-I/MAVS/TBK1, and Toll-like receptors (TLRs). The overall emerging picture is that E6 and E7 have evolved broad-spectrum mechanisms allowing for the simultaneous depletion of multiple rather than single innate immunity effectors. The cGAS/STING/TBK1 pathway appears to be the most heavily impacted, whereas the RIG-I/MAVS/TBK1, still partially functional in HPV-transformed cells, can be activated by the powerful RIG-I agonist M8, triggering the massive production of type I and III interferons (IFNs), which potentiates chemotherapy-mediated cell killing. Overall, the identification of novel therapeutic targets to restore the innate immune response in HPV-transformed cells could transform the way HPV-associated cancers are treated.

Sphingolipids in early viral replication and innate immune activation

2018 ◽  
Vol 399 (10) ◽  
pp. 1115-1123 ◽  
Author(s):  
Judith Bezgovsek ◽  
Erich Gulbins ◽  
Sarah-Kim Friedrich ◽  
Karl S. Lang ◽  
Vikas Duhan
Keyword(s):  
Immune Response ◽  
Viral Replication ◽  
Virus Replication ◽  
Innate Immune Response ◽  
Cell Activation ◽  
Killer Cell ◽  
Virus Multiplication ◽  
Innate Immune ◽  
Type I ◽  
Antiviral Immune Response

Abstract In this review, we summarize the mechanisms by which sphingolipids modulate virus multiplication and the host innate immune response, using a number of host-virus systems as illustrative models. Sphingolipids exert diverse functions, both at the level of the viral life cycle and in the regulation of antiviral immune responses. Sphingolipids may influence viral replication in three ways: by serving as (co)receptors during viral entry, by modulating virus replication, and by shaping the antiviral immune response. Several studies have demonstrated that sphingosine kinases (SphK) and their product, sphingosine-1-phosphate (S1P), enhance the replication of influenza, measles, and hepatitis B virus (HBV). In contrast, ceramides, particularly S1P and SphK1, influence the expression of type I interferon (IFN-I) by modulating upstream antiviral signaling and enhancing dendritic cell maturation, differentiation, and positioning in tissue. The synthetic molecule α-galactosylceramide has also been shown to stimulate natural killer cell activation and interferon (IFN)-γ secretion. However, to date, clinical trials have failed to demonstrate any clinical benefit for sphingolipids in the treatment of cancer or HBV infection. Taken together, these findings show that sphingolipids play an important and underappreciated role in the control of virus replication and the innate immune response.

scholarly journals The Human Papillomavirus E6 Oncoprotein Targets USP15 and TRIM25 To Suppress RIG-I-Mediated Innate Immune Signaling

2017 ◽  
Vol 92 (6) ◽  
Author(s):  
Cindy Chiang ◽  
Eva-Katharina Pauli ◽  
Jennifer Biryukov ◽  
Katharina F. Feister ◽  
Melissa Meng ◽  
...  
Keyword(s):  
Immune Response ◽  
Human Papillomavirus ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Signaling Cascade ◽  
Type I ◽  
Antiviral Immune Response ◽  
Hpv16 E6 ◽  
E6 Oncoprotein ◽  
Hpv16 Infection

ABSTRACTRetinoic acid-inducible gene I (RIG-I) is a key pattern recognition receptor that senses viral RNA and interacts with the mitochondrial adaptor MAVS, triggering a signaling cascade that results in the production of type I interferons (IFNs). This signaling axis is initiated by K63-linked ubiquitination of RIG-I mediated by the E3 ubiquitin ligase TRIM25, which promotes the interaction of RIG-I with MAVS. USP15 was recently identified as an upstream regulator of TRIM25, stabilizing the enzyme through removal of degradative K48-linked polyubiquitin, ultimately promoting RIG-I-dependent cytokine responses. Here, we show that the E6 oncoprotein of human papillomavirus type 16 (HPV16) as well as of other HPV types form a complex with TRIM25 and USP15 in human cells. In the presence of E6, the K48-linked ubiquitination of TRIM25 was markedly increased, and in line with this, TRIM25 degradation was enhanced. Our results further showed that E6 inhibited the TRIM25-mediated K63-linked ubiquitination of RIG-I and its CARD-dependent interaction with MAVS. HPV16 E6, but not E7, suppressed the RIG-I-mediated induction of IFN-β, chemokines, and IFN-stimulated genes (ISGs). Finally, CRISPR-Cas9 gene targeting in human keratinocytes showed that the TRIM25-RIG-I-MAVS triad is important for eliciting an antiviral immune response to HPV16 infection. Our study thus identifies a novel immune escape mechanism that is conserved among different HPV strains and further indicates that the RIG-I signaling pathway plays an important role in the innate immune response to HPV infection.IMPORTANCEPersistent infection and tumorigenesis by HPVs are known to require viral manipulation of a variety of cellular processes, including those involved in innate immune responses. Here, we show that the HPV E6 oncoprotein antagonizes the activation of the cytoplasmic innate immune sensor RIG-I by targeting its upstream regulatory enzymes TRIM25 and USP15. We further show that the RIG-I signaling cascade is important for an antiviral innate immune response to HPV16 infection, providing evidence that RIG-I, whose role in sensing RNA virus infections has been well characterized, also plays a crucial role in the antiviral host response to small DNA viruses of thePapillomaviridaefamily.

scholarly journals Interferon-Inducible LINC02605 Promotes Antiviral Innate Responses by Strengthening IRF3 Nuclear Translocation

2021 ◽  
Vol 12 ◽  
Author(s):  
Rui Xu ◽  
Shuang-Shuang Yu ◽  
Ran-Ran Yao ◽  
Rong-Chun Tang ◽  
Jia-Wei Liang ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Replication ◽  
Innate Immune Response ◽  
Nuclear Translocation ◽  
Rna Virus ◽  
Innate Immune ◽  
Pten Expression ◽  
Type I ◽  
Dependent Manner ◽  
Antiviral Immune Response

Non-coding RNAs represent a class of important regulators in immune response. Previously, LINC02605 was identified as a candidate regulator in innate immune response by lncRNA microarray assays. In this study, we systematically analyzed the functions and the acting mechanisms of LINC02605 in antiviral innate immune response. LINC02605 was up-regulated by RNA virus, DNA virus, and type I IFNs in NF-κB and Jak-stat dependent manner. Overexpression of LINC02605 promotes RNA virus-induced type I interferon production and inhibited viral replication. Consistently, knockdown of LINC02605 resulted in reduced antiviral immune response and increased viral replication. Mechanistically, LINC02605 released the inhibition of hsa-miR-107 on the expression of phosphatase and tensin homolog (PTEN). By microRNA mimics and inhibitors, hsa-miR-107 was demonstrated to not only inhibit PTEN’s expression but also negatively regulate the antiviral immune response. Knockdown of LINC02605 led to the reduction of PTEN expression both in mRNA and protein levels. Overexpression of LINC02605 had an opposite impact. Moreover, LINC02605 attenuated the serine 97 phosphorylation level of interferon regulatory factor 3 (IRF3) by promoting PTEN expression. Nucleoplasmic fragmentation assay showed that knocking down LINC02605 inhibited the nuclear translocation of IRF3, rendering the host cells more susceptible to viral invasion, while overexpression showed opposite effects. Therefore, LINC02605 is an induced lncRNA by viral infection and plays a positive feedback in antiviral immune response through modulating the nuclear translocation of IRF3.

scholarly journals Lymphocytes are detrimental during the early innate immune response against Listeria monocytogenes

2006 ◽  
Vol 203 (4) ◽  
pp. 933-940 ◽  
Author(s):  
Javier A. Carrero ◽  
Boris Calderon ◽  
Emil R. Unanue
Keyword(s):  
Immune Response ◽  
Listeria Monocytogenes ◽  
Innate Immune Response ◽  
Early Stage ◽  
Bacterial Pathogen ◽  
Interleukin 10 ◽  
Innate Immune ◽  
Type I ◽  
Phagocytic Cells ◽  
Immunodeficient Mice

Mice deficient in lymphocytes are more resistant than normal mice to Listeria monocytogenes infection during the early innate immune response. This paradox remains unresolved: lymphocytes are required for sterilizing immunity, but their presence during the early stage of the infection is not an asset and may even be detrimental. We found that lymphocyte-deficient mice, which showed limited apoptosis in infected organs, were resistant during the first four days of infection but became susceptible when engrafted with lymphocytes. Engraftment with lymphocytes from type I interferon receptor–deficient (IFN-αβR−/−) mice, which had reduced apoptosis, did not confer increased susceptibility to infection, even when the phagocytes were IFN-αβR+/+. The attenuation of innate immunity was due, in part, to the production of the antiinflammatory cytokine interleukin 10 by phagocytic cells after the apoptotic phase of the infection. Thus, immunodeficient mice were more resistant relative to normal mice because the latter went through a stage of lymphocyte apoptosis that was detrimental to the innate immune response. This is an example of a bacterial pathogen creating a cascade of events that leads to a permissive infective niche early during infection.

Sign in / Sign up

Export Citation Format

Share Document