TRIM28 facilitates type I interferon activation by targeting TBK1.

Type I interferons play a fundamental role in innate host defense against viral infections by eliciting the induction of an antiviral gene program that serves to inhibit viral replication. Activation of type I interferon is regulated by the IRF3 transcription factor, which undergoes phosphorylation-dependent activation by the upstream kinase, TBK1, during viral infection. However, the mechanisms by which TBK1 achieves activation to support signaling to IRF3 remain incompletely understood.

Autoimmunity as a sequela to obesity and systemic inflammation.

The rising prevalence of obesity presents a world-wide challenge as it is associated with numerous comorbidities including cardiovascular disease, insulin resistance and hypertension. Obesity-associated illnesses are estimated to cause nearly 4 million deaths globally per year, therefore there is a critical need to better understand associated pathogenesis, identify new therapeutic targets, and develop new interventions. Emerging data identify a key role for chronic inflammation in mediating obesity related disease states and reveal higher incidence of autoimmune disease development.

Suppressing fatty acid synthase by type I interferon and chemical inhibitors as a broad spectrum anti-viral strategy against SARS-CoV-2.

SARS-CoV-2 is an emerging viral pathogen and a major global public health challenge since December of 2019, with limited effective treatments throughout the pandemic. As part of the innate immune response to viral infection, type I interferons (IFN-I) trigger a signaling cascade that culminates in the activation of hundreds of genes, known as interferon stimulated genes (ISGs), that collectively foster an antiviral state. We report here the identification of a group of type I interferon suppressed genes, including fatty acid synthase (FASN), which are involved in lipid metabolism.

SARS-CoV-2 Spike Antagonizes Innate Antiviral Immunity by Targeting Interferon Regulatory Factor 3.

Corona virus disease 2019 (COVID-19) pathogenesis is intimately linked to the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) and disease severity has been associated with compromised induction of type I interferon (IFN-I) cytokines which coordinate the innate immune response to virus infections. Here we identified the SARS-CoV-2 encoded protein, Spike, as an inhibitor of IFN-I that antagonizes viral RNA pattern recognition receptor RIG-I signaling. Ectopic expression of SARS-CoV-2 Spike blocked RIG-I mediated activation of IFNβ and downstream induction of interferon stimulated genes.

Azithromycin Protects against Zika virus Infection by Upregulating virus-induced Type I and III Interferon Responses.

Azithromycin (AZM) is a widely used antibiotic, with additional antiviral and anti-inflammatory properties that remain poorly understood. Although Zika virus (ZIKV) poses a significant threat to global health, there are currently no vaccines or effective therapeutics against it. Herein, we report that AZM effectively suppresses ZIKV infection by targeting a late stage in the viral life cycle.

Comprehensive Mutagenesis of Herpes Simplex Virus 1 Genome Identifies UL42 as an Inhibitor of Type I Interferon Induction.

In spite of several decades of research focused on understanding the biology of human herpes simplex virus 1 (HSV-1), no tool has been developed to study its genome in a high-throughput fashion. Here, we describe the creation of a transposon insertion mutant library of the HSV-1 genome. Using this tool, we aimed to identify novel viral regulators of type I interferon (IFN-I).

Autophagy links antimicrobial activity with antigen presentation in Langerhans cells.

DC, through the uptake, processing, and presentation of antigen, are responsible for activation of T cell responses to defend the host against infection, yet it is not known if they can directly kill invading bacteria. Here, we studied in human leprosy, how Langerhans cells (LC), specialized DC, contribute to host defense against bacterial infection. IFN-γ treatment of LC isolated from human epidermis and infected with Mycobacterium leprae (M.

IL-26 contributes to host defense against intracellular bacteria.

IL-26 is an antimicrobial protein secreted by Th17 cells that has the ability to directly kill extracellular bacteria. To ascertain whether IL-26 contributes to host defense against intracellular bacteria, we studied leprosy, caused by the obligate intracellular pathogen Mycobacterium leprae, as a model. Analysis of leprosy skin lesions by gene expression profiling and immunohistology revealed that IL-26 was more strongly expressed in lesions from the self-limited tuberculoid compared with expression in progressive lepromatous patients.

A TRAF3-NIK module differentially regulates DNA vs RNA pathways in innate immune signaling.

Detection of viral genomes by the innate immune system elicits an antiviral gene program mediated by type I interferons (IFNs). While viral RNA and DNA species induce IFN via separate pathways, the mechanisms by which these pathways are differentially modulated are unknown. Here we show that the positive regulator of IFN in the RNA pathway, TRAF3, has an inhibitory function in the DNA pathway.

TAX1BP1 Restrains Virus-Induced Apoptosis by Facilitating Itch-Mediated Degradation of the Mitochondrial Adaptor MAVS.

The host response to RNA virus infection consists of an intrinsic innate immune response and the induction of apoptosis as mechanisms to restrict viral replication. The mitochondrial adaptor molecule MAVS plays critical roles in coordinating both virus-induced type I interferon production and apoptosis; however, the regulation of MAVS-mediated apoptosis is poorly understood. Here, we show that the adaptor protein TAX1BP1 functions as a negative regulator of virus-induced apoptosis.

Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB.

We and others have shown that the cystatin E/M gene is inactivated in primary human tumors, pointing to its role as a tumor suppressor gene. However, the molecular mechanism of tumor suppression is not yet understood. Using plasmid-directed cystatin E/M gene overexpression, a lentivirus-mediated tetracycline-inducible vector system, and human papillomavirus 16 (HPV 16) E6 and E7 gene-immortalized normal human epidermal keratinocytes, we demonstrated intracellular and non-cell-autonomous apoptotic growth inhibition of tumor cell lines and that growth inhibition is associated with cytoplasmic retention of NF-κB.

RING finger protein 11 targets TBK1/IKKi kinases to inhibit antiviral signaling.

A key feature of the innate antiviral immune response is a rapid nonspecific response to virus infection largely mediated by the induction and extracellular secretion of type I interferons (IFNs) that restrict virus replication. Cytoplasmic sensors such as RIG-I recognize viral RNA and trigger antiviral signaling pathways that upregulate IFN transcription. However, it remains largely unknown how antiviral signaling is negatively regulated to maintain homeostasis after the elimination of virus.

The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response.

The induction of type I interferons by the bacterial secondary messengers cyclic di-GMP (c-di-GMP) or cyclic di-AMP (c-di-AMP) is dependent on a signaling axis that involves the adaptor STING, the kinase TBK1 and the transcription factor IRF3. Here we identified the heliase DDX41 as a pattern-recognition receptor (PRR) that sensed both c-di-GMP and c-di-AMP. DDX41 specifically and directly interacted with c-di-GMP.

Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding.

STING is an essential signaling molecule for DNA and cyclic di-GMP (c-di-GMP)-mediated type I interferon (IFN) production via TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) pathway. It contains an N-terminal transmembrane region and a cytosolic C-terminal domain (CTD). Here, we describe crystal structures of STING CTD alone and complexed with c-di-GMP in a unique binding mode.

NOD so fast: NLRX1 puts the brake on inflammation.

In this issue of Immunity, Allen et al. (2011) and Xia et al. (2011) provide in vivo and biochemical evidence that NLRX1, a member of the nucleotide binding domain and leucine-rich-repeat-containing protein family, functions as a negative regulator of RIG-I and Toll-like receptors.

Regulation of inflammatory and antiviral signaling by A20.

The deubiquitinating enzyme A20 (also known as TNFAIP3) is essential for maintaining immune homeostasis. A20 is a key regulator of inflammatory, antiviral and apoptotic signaling pathways. Here, we review recent advances illustrating the role of A20 as an essential negative regulator of inflammatory and antiviral signaling.

TAX1BP1 and A20 inhibit antiviral signaling by targeting TBK1-IKKi kinases.

Induction of type I interferons by the transcription factor IRF3 is essential in the initiation of antiviral innate immunity. Activation of IRF3 requires C-terminal phosphorylation by the upstream kinases TBK1-IKKi, where IRF3 phosphorylation promotes dimerization, and subsequent nuclear translocation to the IFNbeta promoter. Recent studies have described the ubiquitin-editing enzyme A20 as a negative regulator of IRF3 signaling by associating with TBK1-IKKi; however, the regulatory mechanism of A20 inhibition remains unclear.

The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-kappaB signalling.

The RING domain protein RNF11 is overexpressed in breast cancers and promotes tumour growth factor-beta (TGF-beta) signalling. RNF11 has been proposed to regulate TGF-beta signalling by interacting with HECT- and SCF-type E3 ligases; however, the role of RNF11 in other signalling pathways is poorly understood. Here, we demonstrate a novel function of RNF11 as a negative regulator of NF-kappaB and jun N-terminal kinase (JNK) signalling pathways.

The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20.

The ubiquitin-editing enzyme A20 is a critical negative regulator of inflammation and cytokine-mediated activation of the transcription factor NF-kappaB; however, little is known about the mechanisms of A20-mediated inactivation of signaling intermediates such as RIP1. Here we demonstrate that the regulatory molecule TAX1BP1 recruited the E3 ligase Itch to A20 via two 'PPXY' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling A20-mediated recruitment and inactivation of RIP1.

Global analysis of cellular factors and responses involved in Pseudomonas aeruginosa resistance to arsenite.

The impact of arsenite [As(III)] on several levels of cellular metabolism and gene regulation was examined in Pseudomonas aeruginosa. P. aeruginosa isogenic mutants devoid of antioxidant enzymes or defective in various metabolic pathways, DNA repair systems, metal storage proteins, global regulators, or quorum sensing circuitry were examined for their sensitivity to As(III).

Pseudomonas aeruginosa anaerobic respiration in biofilms: relationships to cystic fibrosis pathogenesis.

Recent data indicate that cystic fibrosis (CF) airway mucus is anaerobic. This suggests that Pseudomonas aeruginosa infection in CF reflects biofilm formation and persistence in an anaerobic environment. P.