scholarly journals ­­­Silencing of retrotransposons by SETDB1 inhibits the interferon response in acute myeloid leukemia­­

2017 ◽  
Vol 216 (11) ◽  
pp. 3535-3549 ◽  
Author(s):  
Trinna L. Cuellar ◽  
Anna-Maria Herzner ◽  
Xiaotian Zhang ◽  
Yogesh Goyal ◽  
Colin Watanabe ◽  
...  
Keyword(s):  
Immune System ◽  
Regulatory Networks ◽  
Negative Regulator ◽  
Therapeutic Interventions ◽  
Interferon Response ◽  
Type I ◽  
Cell Propagation ◽  
Screening Platform ◽  
Proliferation Suppression ◽  
Acute Myeloid

A propensity for rewiring genetic and epigenetic regulatory networks, thus enabling sustained cell proliferation, suppression of apoptosis, and the ability to evade the immune system, is vital to cancer cell propagation. An increased understanding of how this is achieved is critical for identifying or improving therapeutic interventions. In this study, using acute myeloid leukemia (AML) human cell lines and a custom CRISPR/Cas9 screening platform, we identify the H3K9 methyltransferase SETDB1 as a novel, negative regulator of innate immunity. SETDB1 is overexpressed in many cancers, and loss of this gene in AML cells triggers desilencing of retrotransposable elements that leads to the production of double-stranded RNAs (dsRNAs). This is coincident with induction of a type I interferon response and apoptosis through the dsRNA-sensing pathway. Collectively, our findings establish a unique gene regulatory axis that cancer cells can exploit to circumvent the immune system.

scholarly journals ETV7 limits antiviral gene expression and control of SARS-CoV-2 and influenza viruses

2019 ◽  
Author(s):  
Heather M. Froggatt ◽  
Alfred T. Harding ◽  
Brook E. Heaton ◽  
Nicholas S. Heaton
Keyword(s):  
Transcription Factor ◽  
Regulatory Networks ◽  
Response Regulator ◽  
Influenza Viruses ◽  
Negative Regulator ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn ◽  
Interferon Stimulated Genes ◽  
Viral Spread

AbstractThe type I interferon (IFN) response is an important component of the innate immune response to viral infection. Precise control of interferon responses is critical; insufficient levels of interferon-stimulated genes (ISGs) can lead to a failure to restrict viral spread while excessive ISG activation can result in interferon-related pathologies. While both positive and negative regulatory factors control the magnitude and duration of IFN signaling, it is also appreciated that a number of ISGs regulate aspects of the interferon response themselves. However, the mechanisms underlying these ISG regulatory networks remain incompletely defined. In this study, we performed a CRISPR activation screen to identify new regulators of the type I IFN response. We identified ETS variant transcription factor 7 (ETV7), a strongly induced ISG, as a protein that acts as a negative regulator of the type I IFN response; however, ETV7 did not uniformly suppress ISG transcription. Instead, ETV7 preferentially targeted a subset of known antiviral ISGs. Further, we showed the subset of ETV7-modulated ISGs was particularly important for IFN-mediated control of some viruses including influenza viruses and SARS-CoV-2. Together, our data assign a function for ETV7 as an IFN response regulator and also identify ETV7 as a therapeutic target to increase innate responses and potentiate the efficacy of interferon-based antiviral therapies.One Sentence SummaryETV7 is an interferon-induced, repressive transcription factor that negatively regulates antiviral interferon-stimulated genes essential for controlling influenza virus and SARS-CoV-2 infections.

scholarly journals NSUN2-mediated m5C methylation of IRF3 mRNA negatively regulates type I interferon responses

2021 ◽  
Author(s):  
Hongyun Wang ◽  
Lu Zhang ◽  
Cong Zeng ◽  
Jiangpeng Feng ◽  
Yu Zhou ◽  
...  
Keyword(s):  
Viral Infection ◽  
Type I Interferon ◽  
Sendai Virus ◽  
Negative Regulator ◽  
Interferon Response ◽  
Rna Modification ◽  
Type I ◽  
Mrna Levels ◽  
Interferon Responses

5-Methylcytosine (m5C) is a widespread post-transcriptional RNA modification and is reported to be involved in manifold cellular responses and biological processes through regulating RNA metabolism. However, its regulatory role in antiviral innate immunity has not yet been elucidated. Here, we report that NSUN2, a typical m5C methyltransferase, can negatively regulate type I interferon responses during viral infection. NSUN2 specifically mediates m5C methylation of IRF3 mRNA and accelerates its degradation, resulting in low levels of IRF3 and downstream IFN-β production. Knockout or knockdown of NSUN2 could enhance type I interferon responses and downstream ISG expression after viral infection in vitro. And in vivo, the antiviral innate responses is more dramatically enhanced in Nsun2+/− mice than in Nsun2+/+ mice. Four highly m5C methylated cytosines in IRF3 mRNA were identified, and their mutation could enhance the cellular IRF3 mRNA levels. Moreover, infection with Sendai virus (SeV), vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), Zika virus (ZIKV), or especially SARS-CoV-2 resulted in a reduction in endogenous levels of NSUN2. Together, our findings reveal that NSUN2 serves as a negative regulator of interferon response by accelerating the fast turnover of IRF3 mRNA, while endogenous NSUN2 levels decrease after viral infection to boost antiviral responses for the effective elimination of viruses. Our results suggest a paradigm of innate antiviral immune responses ingeniously involving NSUN2-mediated m5C modification.

scholarly journals Inflamm-Aging: Why Older Men Are the Most Susceptible to SARS-Cov-2 Complicated Outcomes

2020 ◽  
Author(s):  
Massimiliano Bonafè ◽  
Francesco Prattichizzo ◽  
Angelica Giuliani ◽  
Gianluca Storci ◽  
Jacopo Sabbatinelli ◽  
...  
Keyword(s):  
Immune System ◽  
Systemic Inflammation ◽  
High Mortality ◽  
Older Men ◽  
Interferon Response ◽  
Biological Aging ◽  
Type I ◽  
Immune Senescence ◽  
Elderly Men ◽  
Age Related

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by a high mortality of elderly men with age-related comorbidities. In most of these patients, uncontrolled local and systemic hyperinflammation induces severe and often lethal outcomes. The aging process is characterized by the gradual development of a chronic subclinical systemic inflammation (inflamm-aging) and by acquired immune system impairment (immune senescence). Here, we advance the hypothesis that some key features of aging contribute to the disproportionate SARS-CoV-2 mortality suffered by elderly men. At least four well-recognized aging-related characteristics that are strongly expressed in older men go some way towards explaining why these patients account for the vast majority of fatalities: i. the presence of subclinical systemic inflammation without overt disease, ii. a blunted acquired immune system and type I interferon response due to the chronic inflammation; iii. the downregulation of ACE2 (SARS-CoV-2 receptor), which triggers inflammation, particularly in patients with age-related comorbid diseases such as type II diabetes; and iv. accelerated biological aging, as measured by epigenetic and senescence markers (e.g. telomere shortening) associated to the chronic inflammatory state. Though typical of the aged, especially of elderly men, it is conceivable that these features are also shared by some subsets of the younger population. The high mortality rate of SARS-CoV-2 infection suggests that clarification of the mechanisms of inflamm-aging and immune senescence can help combat not only age-related disorders but also SARS-CoV-2 infection.

scholarly journals Islet expression of type I interferon response sensors is associated with immune infiltration and viral infection in type 1 diabetes

2021 ◽  
Vol 7 (9) ◽  
pp. eabd6527
Author(s):  
Paola S. Apaolaza ◽  
Diana Balcacean ◽  
Jose Zapardiel-Gonzalo ◽  
Grace Nelson ◽  
Nataliya Lenchik ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
Therapeutic Interventions ◽  
Interferon Response ◽  
Type I ◽  
Persistent Infections ◽  
Secretion Pathway ◽  
B Cell Function ◽  
Microbial Stress

Previous results indicate the presence of an interferon (IFN) signature in type 1 diabetes (T1D), capable of inducing chronic inflammation and compromising b cell function. Here, we determined the expression of the IFN response markers MxA, PKR, and HLA-I in the islets of autoantibody-positive and T1D donors. We found that these markers can be coexpressed in the same islet, are more abundant in insulin-containing islets, are highly expressed in islets with insulitis, and their expression levels are correlated with the presence of the enteroviral protein VP1. The expression of these markers was associated with down-regulation of multiple genes in the insulin secretion pathway. The coexistence of an IFN response and a microbial stress response is likely to prime islets for immune destruction. This study highlights the importance of therapeutic interventions aimed at eliminating potentially persistent infections and diminishing inflammation in individuals with T1D.

scholarly journals Molecular and Cellular Function of Transcription Factor 4 in Pitt-Hopkins Syndrome

2021 ◽  
pp. 1-9
Author(s):  
Huei-Ying Chen ◽  
Joseph F. Bohlen ◽  
Brady J. Maher
Keyword(s):  
Transcription Factor ◽  
Regulatory Networks ◽  
Autosomal Dominant ◽  
Autism Spectrum ◽  
Therapeutic Interventions ◽  
Type I ◽  
Helix Loop Helix ◽  
Transcription Factor 4

Transcription factor 4 (TCF4, also known as ITF2 or E2-2) is a type I basic helix-loop-helix transcription factor. Autosomal dominant mutations in TCF4 cause Pitt-Hopkins syndrome (PTHS), a rare syndromic form of autism spectrum disorder. In this review, we provide an update on the progress regarding our understanding of TCF4 function at the molecular, cellular, physiological, and behavioral levels with a focus on phenotypes and therapeutic interventions. We examine upstream and downstream regulatory networks associated with TCF4 and discuss a range of in vitro and in vivo data with the aim of understanding emerging TCF4-specific mechanisms relevant for disease pathophysiology. In conclusion, we provide comments about exciting future avenues of research that may provide insights into potential new therapeutic targets for PTHS.

scholarly journals Au naturale: use of biologically derived cyclic di-nucleotides for cancer immunotherapy

Open Biology ◽  
2021 ◽  
Vol 11 (12) ◽  
Author(s):  
Christopher M. Waters
Keyword(s):  
Immune System ◽  
Cancer Immunotherapy ◽  
Type I Interferon ◽  
Second Messenger ◽  
Interferon Response ◽  
Type I ◽  
Biological Processes ◽  
Signalling Molecules ◽  
Naturally Occurring ◽  
Anti Cancer

Cyclic di-nucleotides (CDNs) are widespread second messenger signalling molecules that regulate fundamental biological processes across the tree of life. These molecules are also potent modulators of the immune system, inducing a Type I interferon response upon binding to the eukaryotic receptor STING. Such a response in tumours induces potent immune anti-cancer responses and thus CDNs are being developed as a novel cancer immunotherapy. In this review, I will highlight the use, challenges and advantages of using naturally occurring CDNs to treat cancer.

scholarly journals A minimal RNA ligand for potent RIG-I activation in living mice

2017 ◽  
Author(s):  
Melissa M. Linehan ◽  
Thayne H. Dickey ◽  
Emanuela S. Molinari ◽  
Megan E. Fitzgerald ◽  
Olga Potapova ◽  
...  
Keyword(s):  
Immune System ◽  
Type I Interferons ◽  
Poly I:C ◽  
Interferon Response ◽  
Type I ◽  
Base Pairs ◽  
Stem Loop ◽  
Interferon Stimulated Genes ◽  
Rna Sensors

AbstractWe have developed highly potent synthetic activators of the vertebrate immune system that specifically target the RIG-I receptor. When introduced into mice, a family of short, triphosphorylated Stem Loop RNAs (SLRs) induces a potent interferon response and the activation of specific genes essential for antiviral defense. Using RNAseq, we provide the first in-vivo genome-wide view of the expression networks that are initiated upon RIG-I activation. We observe that SLRs specifically induce type I interferons, subsets of interferon-stimulated genes (ISGs), and cellular remodeling factors. By contrast, poly(I:C), which binds and activates multiple RNA sensors, induces type III interferons and several unique ISGs. The short length (10-14 base pairs) and robust function of SLRs in mice demonstrate that RIG-I forms active signaling complexes without oligomerizing on RNA. These findings demonstrate that SLRs are potent therapeutic and investigative tools for targeted modulation of the innate immune system.

scholarly journals USP18 – a multifunctional component in the interferon response

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Anja Basters ◽  
Klaus-Peter Knobeloch ◽  
Günter Fritz
Keyword(s):  
Type I Interferon ◽  
Current Knowledge ◽  
Negative Regulator ◽  
Interferon Response ◽  
Structural Basis ◽  
Type I ◽  
Deubiquitinating Enzymes ◽  
Bifunctional Protein ◽  
Isopeptide Bond ◽  
Independent Functions

Ubiquitin-specific proteases (USPs) represent the largest family of deubiquitinating enzymes (DUB). These proteases cleave the isopeptide bond between ubiquitin and a lysine residue of a ubiquitin-modified protein. USP18 is a special member of the USP family as it only deconjugates the ubiquitin-like protein ISG15 (interferon-stimulated gene (ISG) 15) from target proteins but is not active towards ubiquitin. Independent of its protease activity, USP18 functions as a major negative regulator of the type I interferon response showing that USP18 is – at least – a bifunctional protein. In this review, we summarise our current knowledge of protease-dependent and -independent functions of USP18 and discuss the structural basis of its dual activity.

scholarly journals Friend retrovirus studies reveal complex interactions between intrinsic, innate and adaptive immunity

2019 ◽  
Vol 43 (5) ◽  
pp. 435-456 ◽  
Author(s):  
Ulf Dittmer ◽  
Kathrin Sutter ◽  
George Kassiotis ◽  
Gennadiy Zelinskyy ◽  
Zoltán Bánki ◽  
...  
Keyword(s):  
Immune System ◽  
Adaptive Immunity ◽  
Molecular Mechanisms ◽  
Vaccine Development ◽  
Acute Infection ◽  
Therapeutic Interventions ◽  
Type I Interferons ◽  
Type I ◽  
Retroviral Infection ◽  
Innate And Adaptive Immunity

ABSTRACTApproximately 4.4% of the human genome is comprised of endogenous retroviral sequences, a record of an evolutionary battle between man and retroviruses. Much of what we know about viral immunity comes from studies using mouse models. Experiments using the Friend virus (FV) model have been particularly informative in defining highly complex anti-retroviral mechanisms of the intrinsic, innate and adaptive arms of immunity. FV studies have unraveled fundamental principles about how the immune system controls both acute and chronic viral infections. They led to a more complete understanding of retroviral immunity that begins with cellular sensing, production of type I interferons, and the induction of intrinsic restriction factors. Novel mechanisms have been revealed, which demonstrate that these earliest responses affect not only virus replication, but also subsequent innate and adaptive immunity. This review on FV immunity not only surveys the complex host responses to a retroviral infection from acute infection to chronicity, but also highlights the many feedback mechanisms that regulate and counter-regulate the various arms of the immune system. In addition, the discovery of molecular mechanisms of immunity in this model have led to therapeutic interventions with implications for HIV cure and vaccine development.

scholarly journals TRIM14 is a key regulator of the type I interferon response during Mycobacterium tuberculosis infection

2019 ◽  
Author(s):  
Caitlyn T. Hoffpauir ◽  
Samantha L. Bell ◽  
Kelsi O. West ◽  
Tao Jing ◽  
Sylvia Torres-Odio ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Nucleic Acid ◽  
Type I Interferon ◽  
Negative Regulator ◽  
Interferon Response ◽  
Cytokine Signaling ◽  
Type I ◽  
Type I Ifn ◽  
Mycobacterium Tuberculosis Infection ◽  
Innate Immune Signaling

ABSTRACTTripartite motif-containing proteins (TRIMs) play a variety of recently described roles in innate immunity. While many TRIMs regulate type I interferon (IFN) expression following cytosolic nucleic acid sensing of viruses, their contribution to innate immune signaling and gene expression during bacterial infection remains largely unknown. Because Mycobacterium tuberculosis is a potent activator of cGAS-dependent cytosolic DNA sensing, we set out to investigate a role for TRIM proteins in regulating macrophage responses to M. tuberculosis. Here we demonstrate that TRIM14, a non-canonical TRIM that lacks an E3 ligase RING domain, is a critical negative regulator of the type I IFN response in macrophages. We show that TRIM14 physically interacts with both cGAS and TBK1 and that macrophages lacking TRIM14 dramatically hyperinduce interferon stimulated gene (ISG) expression following cytosolic nucleic acid transfection, IFN-β treatment, and M. tuberculosis infection. Consistent with a defect in resolution of the type I IFN response, Trim14 knockout (KO) macrophages have more phospho-Ser754 STAT3 relative to phospho-727 and fail to upregulate the STAT3 target Socs3 (Suppressor of Cytokine Signaling 3), which is required to turn off IFNAR signaling. These data support a model whereby TRIM14 acts as a scaffold between TBK1 and STAT3 to promote phosphorylation of STAT3 at Ser727 and enhance negative regulation of ISG expression. Remarkably, Trim14 KO macrophages hyperinduce antimicrobials like Inos2 and are significantly better than control cells at limiting M. tuberculosis replication. Collectively, these data reveal a previously unappreciated role for TRIM14 in resolving type I IFN responses and controlling M. tuberculosis infection.

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