scholarly journals The Regulatory Network of Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Pathway in Viral Evasion

2021 ◽  
Vol 12 ◽  
Author(s):  
Tongyu Hu ◽  
Mingyu Pan ◽  
Yue Yin ◽  
Chen Wang ◽  
Ye Cui ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Cyclic Gmp ◽  
Mammalian Cells ◽  
Type I Interferon ◽  
Viral Proteins ◽  
Current Status ◽  
Type I ◽  
Non Coding Rnas ◽  
Sting Pathway ◽  
Viral Evasion

Virus infection has been consistently threatening public health. The cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway is a critical defender to sense various pathogens and trigger innate immunity of mammalian cells. cGAS recognizes the pathogenic DNA in the cytosol and then synthesizes 2′3′-cyclic GMP-AMP (2′3′cGAMP). As the second messenger, cGAMP activates STING and induces the following cascade to produce type I interferon (IFN-I) to protect against infections. However, viruses have evolved numerous strategies to hinder the cGAS-STING signal transduction, promoting their immune evasion. Here we outline the current status of the viral evasion mechanism underlying the regulation of the cGAS-STING pathway, focusing on how post-transcriptional modifications, viral proteins, and non-coding RNAs involve innate immunity during viral infection, attempting to inspire new targets discovery and uncover potential clinical antiviral treatments.

scholarly journals ABCC1/MRP1 exports cGAMP and modulates cGAS-dependent immunity

2021 ◽  
Author(s):  
Joanna H. Maltbaek ◽  
Jessica M. Snyder ◽  
Daniel B. Stetson
Keyword(s):  
Mouse Model ◽  
Cyclic Gmp ◽  
Regulatory Mechanism ◽  
Type I Interferon ◽  
Type I ◽  
Adapter Protein ◽  
Dna Sensor ◽  
Interferon Production ◽  
Sting Pathway ◽  
Cyclic Dinucleotide

AbstractThe DNA sensor cyclic GMP-AMP synthase (cGAS) is important for antiviral and anti-tumor immunity. cGAS generates cyclic GMP-AMP (cGAMP), a diffusible cyclic dinucleotide that activates the antiviral response through the adapter protein Stimulator of Interferon Genes (STING). cGAMP is negatively charged and cannot passively cross cell membranes, but recent advances have established a role for extracellular cGAMP as an “immunotransmitter” that can be imported into cells. However, the mechanism by which cGAMP exits cells remains unknown. Here, we identify ABCC1/MRP1 as an ATP-dependent cGAMP exporter that influences STING signaling and type I interferon production. We demonstrate that ABCC1 deficiency exacerbates cGAS-dependent autoimmunity in the Trex1-/- mouse model of Aicardi-Goutières syndrome. These studies identify ABCC1-mediated cGAMP export as a key regulatory mechanism of the cGAS-STING pathway.

scholarly journals B.1.1.7 and B.1.351 SARS-CoV-2 variants display enhanced Spike-mediated fusion

2021 ◽  
Author(s):  
Maaran Michael Rajah ◽  
Mathieu Hubert ◽  
Elodie Bishop ◽  
Nell Saunders ◽  
Rémy Robinot ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Monoclonal Antibodies ◽  
Reference Strain ◽  
Type I Interferon ◽  
Transmembrane Proteins ◽  
Viral Proteins ◽  
Type I ◽  
Cytopathic Effects ◽  
Lung Abnormalities ◽  
Infected Cells

SARS-CoV-2 B.1.1.7 (variant Alpha) and B.1.351 (variant Beta) have supplanted pre-existing strains in many countries. Severe COVID-19 is characterized by lung abnormalities, including the presence of syncytial pneumocytes. Syncytia form when infected cells fuse with adjacent cells. The fitness, cytopathic effects and type-I interferon (IFN) sensitivity of the variants remain poorly characterized. Here, we assessed B.1.1.7 and B.1.351 spread and fusion in cell cultures. B.1.1.7 and B.1.351 replicated similarly to D614G reference strain in Vero, Caco-2, Calu-3 and primary airway cells and were similarly sensitive to IFN. The variants formed larger and more numerous syncytia. Variant Spikes, in the absence of any other viral proteins, resulted in faster fusion relative to D614G. B.1.1.7 and B.1.351 fusion was similarly inhibited by interferon induced transmembrane proteins (IFITMs). Individual mutations present in the variant Spikes modified fusogenicity, binding to ACE2 and recognition by monoclonal antibodies. Also, B.1.1.7 and B.1.351 variants remain sensitive to innate immunity components. The mutations present in the two variants globally enhance viral fusogenicity and allow for antibody evasion.

scholarly journals TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity

2015 ◽  
Vol 210 (6) ◽  
pp. 973-989 ◽  
Author(s):  
Tomonori Kimura ◽  
Ashish Jain ◽  
Seong Won Choi ◽  
Michael A. Mandell ◽  
Kate Schroder ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Mammalian Cells ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Key Factors ◽  
Autophagic Degradation ◽  
Response Systems ◽  
Mediterranean Fever ◽  
Trim Proteins

The present paradigms of selective autophagy in mammalian cells cannot fully explain the specificity and selectivity of autophagic degradation. In this paper, we report that a subset of tripartite motif (TRIM) proteins act as specialized receptors for highly specific autophagy (precision autophagy) of key components of the inflammasome and type I interferon response systems. TRIM20 targets the inflammasome components, including NLRP3, NLRP1, and pro–caspase 1, for autophagic degradation, whereas TRIM21 targets IRF3. TRIM20 and TRIM21 directly bind their respective cargo and recruit autophagic machinery to execute degradation. The autophagic function of TRIM20 is affected by mutations associated with familial Mediterranean fever. These findings broaden the concept of TRIMs acting as autophagic receptor regulators executing precision autophagy of specific cytoplasmic targets. In the case of TRIM20 and TRIM21, precision autophagy controls the hub signaling machineries and key factors, inflammasome and type I interferon, directing cardinal innate immunity response systems in humans.

scholarly journals Development of Small-Molecule STING Activators for Cancer Immunotherapy

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 33
Author(s):  
Hee Ra Jung ◽  
Seongman Jo ◽  
Min Jae Jeon ◽  
Hyelim Lee ◽  
Yeonjeong Chu ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Cyclic Gmp ◽  
Therapeutic Potential ◽  
Interferon Response ◽  
Type I ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Sting Pathway

In cancer immunotherapy, the cyclic GMP–AMP synthase–stimulator of interferon genes (STING) pathway is an attractive target for switching the tumor immunophenotype from ‘cold’ to ‘hot’ through the activation of the type I interferon response. To develop a new chemical entity for STING activator to improve cyclic GMP-AMP (cGAMP)-induced innate immune response, we identified KAS-08 via the structural modification of DW2282, which was previously reported as an anti-cancer agent with an unknown mechanism. Further investigation revealed that direct STING binding or the enhanced phosphorylation of STING and downstream effectors were responsible for DW2282-or KAS-08-mediated STING activity. Furthermore, KAS-08 was validated as an effective STING pathway activator in vitro and in vivo. The synergistic effect of cGAMP-mediated immunity and efficient anti-cancer effects successfully demonstrated the therapeutic potential of KAS-08 for combination therapy in cancer treatment.

scholarly journals Inactivation of the type I interferon pathway reveals long double‐stranded RNA ‐mediated RNA interference in mammalian cells

2016 ◽  
Vol 35 (23) ◽  
pp. 2505-2518 ◽  
Author(s):  
Pierre V Maillard ◽  
Annemarthe G Van der Veen ◽  
Safia Deddouche‐Grass ◽  
Neil C Rogers ◽  
Andres Merits ◽  
...  
Keyword(s):  
Rna Interference ◽  
Mammalian Cells ◽  
Type I Interferon ◽  
Type I ◽  
Double Stranded Rna ◽  
Interferon Pathway

scholarly journals Type I Interferon Regulates the Expression of Long Non-Coding RNAs

2014 ◽  
Vol 5 ◽  
Author(s):  
Elena Carnero ◽  
Marina Barriocanal ◽  
Victor Segura ◽  
Elizabeth Guruceaga ◽  
Celia Prior ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Type I ◽  
Non Coding Rnas

scholarly journals Mammalian Casein Kinase 1α and Its Leishmanial Ortholog Regulate Stability of IFNAR1 and Type I Interferon Signaling

2009 ◽  
Vol 29 (24) ◽  
pp. 6401-6412 ◽  
Author(s):  
Jianghuai Liu ◽  
Lucas P. Carvalho ◽  
Sabyasachi Bhattacharya ◽  
Christopher J. Carbone ◽  
K. G. Suresh Kumar ◽  
...  
Keyword(s):  
Er Stress ◽  
Mammalian Cells ◽  
Leishmania Major ◽  
Type I Interferon ◽  
Casein Kinase ◽  
Type I ◽  
Bona Fide ◽  
Activity Dependent

ABSTRACT Phosphorylation of the degron of the IFNAR1 chain of the type I interferon (IFN) receptor triggers ubiquitination and degradation of this receptor and, therefore, plays a crucial role in negative regulation of IFN-α/β signaling. Besides the IFN-stimulated and Jak activity-dependent pathways, a basal ligand-independent phosphorylation of IFNAR1 has been described and implicated in downregulating IFNAR1 in response to virus-induced endoplasmic reticulum (ER) stress. Here we report purification and characterization of casein kinase 1α (CK1α) as a bona fide major IFNAR1 kinase that confers basal turnover of IFNAR1 and cooperates with ER stress stimuli to mediate phosphorylation-dependent degradation of IFNAR1. Activity of CK1α was required for phosphorylation and downregulation of IFNAR1 in response to ER stress and viral infection. While many forms of CK1 were capable of phosphorylating IFNAR1 in vitro, human CK1α and L-CK1 produced by the protozoan Leishmania major were also capable of increasing IFNAR1 degron phosphorylation in cells. Expression of leishmania CK1 in mammalian cells stimulated the phosphorylation-dependent downregulation of IFNAR1 and attenuated its signaling. Infection of mammalian cells with L. major modestly decreased IFNAR1 levels and attenuated cellular responses to IFN-α in vitro. We propose a role for mammalian and parasite CK1 enzymes in regulating IFNAR1 stability and type I IFN signaling.

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