When your cap matters: structural insights into self vs non-self recognition of 5′ RNA by immunomodulatory host proteins

Leung, Daisy W.; Amarasinghe, Gaya K.

doi:10.1016/j.sbi.2016.02.001

Cited by 63 publications

(70 citation statements)

References 67 publications

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“…Besides associating with 5¢ PPP-RNA, IFIT1 has the ability to directly associate with capped RNA that lacks a methylation mark at the first ribose (2¢O N1 unmethylated RNA) (Habjan and others 2013; Kumar and 190 GEBHARDT, LAUDENBACH, AND PICHLMAIR others 2014). Viruses that fail to methylate the 2¢O position of the first ribose are attenuated in wild-type mice but are highly pathogenic in IFIT-deficient animals (Daffis and others 2010;Leung and Amarasinghe 2016). It is yet not entirely clear how IFIT1 and -5 impair virus growth but the high amounts of IFIT proteins expressed after IFN treatment suggests stoichiometric interference with viral nucleic acids rather than enzymatic activity of IFIT proteins (Habjan and others 2013;Kumar and others 2014).…”

Section: Direct Effectors Of Viral Nucleic Acidsmentioning

confidence: 99%

Discrimination of Self and Non-Self Ribonucleic Acids

Gebhardt

Laudenbach

Pichlmair

2017

Journal of Interferon & Cytokine Research

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Most virus infections are controlled through the innate and adaptive immune system. A surprisingly limited number of so-called pattern recognition receptors (PRRs) have the ability to sense a large variety of virus infections. The reason for the broad activity of PRRs lies in the ability to recognize viral nucleic acids. These nucleic acids lack signatures that are present in cytoplasmic cellular nucleic acids and thereby marking them as pathogen-derived. Accumulating evidence suggests that these signatures, which are predominantly sensed by a class of PRRs called retinoic acid-inducible gene I (RIG-I)-like receptors and other proteins, are not unique to viruses but rather resemble immature forms of cellular ribonucleic acids generated by cellular polymerases. RIG-I-like receptors, and other cellular antiviral proteins, may therefore have mainly evolved to sense nonprocessed nucleic acids typically generated by primitive organisms and pathogens. This capability has not only implications on induction of antiviral immunity but also on the function of cellular proteins to handle selfderived RNA with stimulatory potential.

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Section: Direct Effectors Of Viral Nucleic Acidsmentioning

confidence: 99%

Discrimination of Self and Non-Self Ribonucleic Acids

Gebhardt

Laudenbach

Pichlmair

2017

Journal of Interferon & Cytokine Research

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“…Pathogen-associated molecular patterns (PAMPs) in viruses include single-stranded and double-stranded nucleic acids that are detected by pattern recognition receptors (PRRs) such as Toll-like receptors (TLR3, TLR7, TLR8, and TLR9), RIG-I-like receptors (RIG-I and MDA5), and DNA sensors (cGAS, DAI, and IFI16) (Cai et al, 2014; Kawai and Akira, 2006; Keating et al, 2011; Leung and Amarasinghe, 2016). PRR binding of viral PAMPs triggers signaling cascades that induce the expression of immunomodulatory and antiviral genes including type I interferons (IFN).…”

Section: Introductionmentioning

confidence: 99%

Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability

et al. 2018

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SUMMARY Interferon-induced proteins with tetratricopeptide repeats (IFIT) inhibit infection of many viruses by recognizing their RNA, but the mechanisms regulating their remain unclear. We report a crystal structure of cap 0 (m7GpppN)-RNA-bound to human IFIT1 in complex with the C-terminal domain of human IFIT3. Structural, biochemical, and genetic studies suggest that IFIT3 binding to IFIT1 has dual regulatory functions: (a) extending the half-life of IFIT1, which increases its steady-state levels in cells and (b) allosterically regulating the IFIT1 RNA-binding channel, which enhances the specificity of recognition for cap 0 but not cap 1 (m7GpppNm) or 5′-ppp RNA. Mouse Ifit3 lacks this key C-terminal domain and does not bind mouse Ifit1. The IFIT3 interaction with IFIT1 was important for restricting infection of viruses lacking 2′-O methylation in their RNA cap structures. Our experiments establish differences in regulation of IFIT1 orthologs and define targets for modulating the activity of human IFIT proteins.

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“…For example, cytosolic RNAs derived from invading RNA viruses are detected by RIG-I and MDA5 in the cytosol (Kato et al, 2005; Kato et al, 2006; Weber-Gerlach and Weber, 2016; Yoneyama et al, 2004). Although there are also numerous host messenger RNAs in the cytosolic compartment, RIG-I and MDA5 respond to viral RNAs tri-phosphorylated in their 5’ ends (Leung and Amarasinghe, 2016; Lu et al, 2010; Marq et al, 2011; Wang et al, 2010). Therefore, the host develops delicate machineries to distinguish self-components from non-self-components, which is the principle of innate immune responses.…”

Section: Introductionmentioning

confidence: 99%

DNA sensor cGAS-mediated immune recognition

et al. 2016

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The host takes use of pattern recognition receptors (PRRs) to defend against pathogen invasion or cellular damage. Among microorganism-associated molecular patterns detected by host PRRs, nucleic acids derived from bacteria or viruses are tightly supervised, providing a fundamental mechanism of host defense. Pathogenic DNAs are supposed to be detected by DNA sensors that induce the activation of NFκB or TBK1-IRF3 pathway. DNA sensor cGAS is widely expressed in innate immune cells and is a key sensor of invading DNAs in several cell types. cGAS binds to DNA, followed by a conformational change that allows the synthesis of cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) from adenosine triphosphate and guanosine triphosphate. cGAMP is a strong activator of STING that can activate IRF3 and subsequent type I interferon production. Here we describe recent progresses in DNA sensors especially cGAS in the innate immune responses against pathogenic DNAs.

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When your cap matters: structural insights into self vs non-self recognition of 5′ RNA by immunomodulatory host proteins

Cited by 63 publications

References 67 publications

Discrimination of Self and Non-Self Ribonucleic Acids

Discrimination of Self and Non-Self Ribonucleic Acids

Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability

DNA sensor cGAS-mediated immune recognition

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