Nucleic Acid Sensing and Innate Immunity: Signaling Pathways Controlling Viral Pathogenesis and Autoimmunity

Ahlers, Laura R. H.; Goodman, Alan G.

doi:10.1007/s40588-016-0043-5

Cited by 16 publications

(11 citation statements)

References 110 publications

(109 reference statements)

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“…One primary limiting factor in the evolution of large RNA structures could have been the surveillance by the immune system. Nucleic acid multimerization often triggers innate immune responses [ 184 , 185 , 186 , 187 ]. In mammals, viral dsRNA is recognized by several families of proteins involved in innate immunity, including RIG-I, MDA5, TLR3, LGP2, PKR, etc.…”

Section: Rna Multimerization In Disease and Immunitymentioning

confidence: 99%

Structural Insights into RNA Dimerization: Motifs, Interfaces and Functions

Bou‐Nader

Zhang

2020

Molecules

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In comparison with the pervasive use of protein dimers and multimers in all domains of life, functional RNA oligomers have so far rarely been observed in nature. Their diminished occurrence contrasts starkly with the robust intrinsic potential of RNA to multimerize through long-range base-pairing (“kissing”) interactions, self-annealing of palindromic or complementary sequences, and stable tertiary contact motifs, such as the GNRA tetraloop-receptors. To explore the general mechanics of RNA dimerization, we performed a meta-analysis of a collection of exemplary RNA homodimer structures consisting of viral genomic elements, ribozymes, riboswitches, etc., encompassing both functional and fortuitous dimers. Globally, we found that domain-swapped dimers and antiparallel, head-to-tail arrangements are predominant architectural themes. Locally, we observed that the same structural motifs, interfaces and forces that enable tertiary RNA folding also drive their higher-order assemblies. These feature prominently long-range kissing loops, pseudoknots, reciprocal base intercalations and A-minor interactions. We postulate that the scarcity of functional RNA multimers and limited diversity in multimerization motifs may reflect evolutionary constraints imposed by host antiviral immune surveillance and stress sensing. A deepening mechanistic understanding of RNA multimerization is expected to facilitate investigations into RNA and RNP assemblies, condensates, and granules and enable their potential therapeutical targeting.

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Section: Rna Multimerization In Disease and Immunitymentioning

confidence: 99%

Structural Insights into RNA Dimerization: Motifs, Interfaces and Functions

Bou‐Nader

Zhang

2020

Molecules

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“…Our knowledge of the antiviral functions of ISGs was greatly expanded with several recent investigations that tested hundreds of ISGs for their inhibition of a wide range of viruses [ 28 , 29 , 30 , 31 , 32 ]. In addition to direct inhibition of viruses, some ISGs are professional viral sensors, such as RIG-I, PKR, IFI16, cGAS and others [ 33 , 34 ]. Beyond all these functions and mechanisms, an emerging new antiviral strategy employed by ISGs is to modulate cellular metabolic pathways, including the synthesis of cholesterol, polyamines and tryptophan.…”

Section: Diverse Antiviral Mechanisms By Interferons and Their Stimentioning

confidence: 99%

Interferons: Reprogramming the Metabolic Network against Viral Infection

Raniga

Liang

2018

Viruses

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Viruses exploit the host and induce drastic metabolic changes to ensure an optimal environment for replication and the production of viral progenies. In response, the host has developed diverse countermeasures to sense and limit these alterations to combat viral infection. One such host mechanism is through interferon signaling. Interferons are cytokines that enhances the transcription of hundreds of interferon-stimulated genes (ISGs) whose products are key players in the innate immune response to viral infection. In addition to their direct targeting of viral components, interferons and ISGs exert profound effects on cellular metabolism. Recent studies have started to illuminate on the specific role of interferon in rewiring cellular metabolism to activate immune cells and limit viral infection. This review reflects on our current understanding of the complex networking that occurs between the virus and host at the interface of cellular metabolism, with a focus on the ISGs in particular, cholesterol-25-hydroxylase (CH25H), spermidine/spermine acetyltransferase 1 (SAT1), indoleamine-2,3-dioxygenase (IDO1) and sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1), which were recently discovered to modulate specific metabolic events and consequently deter viral infection.

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“…The deployment of pattern recognition receptors (PRRs) is the primary method for the innate immune system to detect pathogens or cellular damage via their associated molecular patterns (PAMPs and DAMPs) 1 . Among PRRs are cytoplasmic RNA and DNA nucleic acid sensors [2][3][4][5][6][7][8][9] . Nucleic acids from incoming pathogens have distinct molecular features that are recognized by host PRRs localized within the cytosol 10 .…”

Section: Introductionmentioning

confidence: 99%

Small molecule inhibition of human cGAS reduces total cGAMP output and cytokine expression in cells

Wiser

Kim

Vincent

et al. 2020

Preprint

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ABSTRACTThe cGAS-STING pathway is a major mechanism that mammalian cells utilize to detect cytoplasmic dsDNA from incoming viruses, bacteria, or self. CYCLIC GMP-AMP SYNTHASE (cGAS) is the sensor protein that directly binds dsDNAs. cGAS synthesizes cyclic GMP-AMP (cGAMP), which binds to the adaptor STIMULATOR OF INTERFERON GENES (STING), activating an INTERFERON REGULATORY FACTOR 3 (IRF3)-mediated immune response. Constitutive activation can result in interferonopathies such as Aicardi-Goutieres Syndrome (AGS) or other lupus-like autoimmune disorders. While inhibitors targeting mouse or human cGAS have been reported, the identification of a small molecule that targets both homologs of cGAS has been challenging. Here, we show that RU.521 is capable of potently and selectively inhibiting mouse and human cGAS in cell lines and human primary cells. This inhibitory activity requires the presence of cGAS, but it cannot suppress an immune response in cells activated by RNA, Toll-like receptor ligands, cGAMP, or recombinant interferon. Importantly, when RU.521 is applied to cells, the production of dsDNA-induced intracellular cGAMP is suppressed in a dose-dependent manner. Our work validates the use of RU.521 for probing DNA-induced innate immune responses and underscores its potential as an ideal scaffold towards pre-clinical development, given its potency against human and mouse cGAS.

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Nucleic Acid Sensing and Innate Immunity: Signaling Pathways Controlling Viral Pathogenesis and Autoimmunity

Cited by 16 publications

References 110 publications

Structural Insights into RNA Dimerization: Motifs, Interfaces and Functions

Structural Insights into RNA Dimerization: Motifs, Interfaces and Functions

Interferons: Reprogramming the Metabolic Network against Viral Infection

Small molecule inhibition of human cGAS reduces total cGAMP output and cytokine expression in cells

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