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1.
Mol Cell ; 83(1): 90-104.e4, 2023 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-36521492

RESUMEN

RIG-I is essential for host defense against viral pathogens, as it triggers the release of type I interferons upon encounter with viral RNA molecules. In this study, we show that RIG-I is rapidly and efficiently activated by small quantities of incoming viral RNA and that it relies exclusively on the constitutively expressed resident pool of RIG-I receptors for a strong antiviral response. Live-cell imaging of RIG-I following stimulation with viral or synthetic dsRNA reveals that RIG-I signaling occurs without mass aggregation at the mitochondrial membrane. By contrast, interferon-induced RIG-I protein becomes embedded in cytosolic aggregates that are functionally unrelated to signaling. These findings suggest that endogenous RIG-I efficiently recognizes viral RNA and rapidly relays an antiviral signal to MAVS via a transient signaling complex and that cellular aggregates of RIG-I have a function that is distinct from signaling.


Asunto(s)
Interferón Tipo I , Transducción de Señal , Transducción de Señal/genética , Proteína 58 DEAD Box/genética , Proteína 58 DEAD Box/metabolismo , Antivirales/farmacología , Interferón Tipo I/genética , ARN Bicatenario/genética , ARN Viral/genética , Inmunidad Innata
2.
Immunol Rev ; 304(1): 154-168, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34514601

RESUMEN

RIG-I is our first line of defense against RNA viruses, serving as a pattern recognition receptor that identifies molecular features common among dsRNA and ssRNA viral pathogens. RIG-I is maintained in an inactive conformation as it samples the cellular space for pathogenic RNAs. Upon encounter with the triphosphorylated terminus of blunt-ended viral RNA duplexes, the receptor changes conformation and releases a pair of signaling domains (CARDs) that are selectively modified and interact with an adapter protein (MAVS), thereby triggering a signaling cascade that stimulates transcription of interferons. Here, we describe the structural determinants for specific RIG-I activation by viral RNA, and we describe the strategies by which RIG-I remains inactivated in the presence of host RNAs. From the initial RNA triggering event to the final stages of interferon expression, we describe the experimental evidence underpinning our working knowledge of RIG-I signaling. We draw parallels with behavior of related proteins MDA5 and LGP2, describing evolutionary implications of their collective surveillance of the cell. We conclude by describing the cell biology and immunological investigations that will be needed to accurately describe the role of RIG-I in innate immunity and to provide the necessary foundation for pharmacological manipulation of this important receptor.


Asunto(s)
ARN Helicasas DEAD-box , ARN Bicatenario , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Inmunidad Innata , Helicasa Inducida por Interferón IFIH1/genética , ARN Viral , Transducción de Señal
3.
bioRxiv ; 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-39026721

RESUMEN

Mapping the genomic architecture of complex disease has been predicated on the understanding that genetic variants influence disease risk through modifying gene expression. However, recent discoveries have revealed that a significant burden of disease heritability in common autoinflammatory disorders and coronary artery disease is mediated through genetic variation modifying post-transcriptional modification of RNA through adenosine-to-inosine (A-to-I) RNA editing. This common RNA modification is catalyzed by ADAR enzymes, where ADAR1 edits specific immunogenic double stranded RNA (dsRNA) to prevent activation of the double strand RNA (dsRNA) sensor MDA5 ( IFIH1 ) and stimulation of an interferon stimulated gene (ISG) response. Multiple lines of human genetic data indicate impaired RNA editing and increased dsRNA sensing to be an important mechanism of coronary artery disease (CAD) risk. Here, we provide a crucial link between observations in human genetics and mechanistic cell biology leading to progression of CAD. Through analysis of human atherosclerotic plaque, we implicate the vascular smooth muscle cell (SMC) to have a unique requirement for RNA editing, and that ISG induction occurs in SMC phenotypic modulation, implicating MDA5 activation. Through culture of human coronary artery SMCs, generation of a conditional SMC specific Adar1 deletion mouse model on a pro-atherosclerosis background, and with incorporation of single cell RNA sequencing cellular profiling, we further show that Adar1 controls SMC phenotypic state, is required to maintain vascular integrity, and controls progression of atherosclerosis and vascular calcification. Through this work, we describe a fundamental mechanism of CAD, where cell type and context specific RNA editing and sensing of dsRNA mediates disease progression, bridging our understanding of human genetics and disease causality.

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