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  • Review Article
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Cellular origins of dsRNA, their recognition and consequences

Nature Reviews Molecular Cell Biology volume 23, pages 286–301 (2022)Cite this article

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Abstract

Double-stranded RNA (dsRNA) is associated with most viral infections — it either constitutes the viral genome (in the case of dsRNA viruses) or is generated in host cells during viral replication. Hence, nearly all organisms have the capability of recognizing dsRNA and mounting a response, the primary aim of which is to mitigate the potential infection. In vertebrates, a set of innate immune receptors for dsRNA induce a multitude of cell-intrinsic and cell-extrinsic immune responses upon dsRNA recognition. Notably, recent studies showed that vertebrate cells can accumulate self-derived dsRNAs or dsRNA-like species upon dysregulation of several cellular processes, activating the very same immune pathways as in infected cells. On the one hand, such aberrant immune activation in the absence of infection can lead to pathogenesis of immune disorders, such as Aicardi–Goutières syndrome. On the other hand, the same innate immune reaction can be induced in a controlled setting for a therapeutic benefit, as occurs in immunotherapies. In this Review, we describe mechanisms by which immunostimulatory dsRNAs are generated in mammalian cells, either by viruses or by the host cells, and how cells respond to them, with the focus on recent developments regarding the role of cellular dsRNAs in immune modulation.

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Fig. 1: dsRNA sensors and their signalling.
Fig. 2: RNA modifications affect the RNA’s secondary structures and interaction with immune sensors.
Fig. 3: Endogenous sources of dsRNA and cellular regulatory processes.
Fig. 4: Consequences of dsRNA recognition.

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Acknowledgements

S.H. was supported by the NIH (R01AI154653, R01AI111784 and DP1AI152074). Y.G.C. was supported by the NIH (R35GM142687 and 5K12CA215110), the Rita Allen Foundation and the Yale Cancer Center.

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  1. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA

    Y. Grace Chen

  2. Harvard Medical School & Boston Children’s Hospital, Boston, MA, USA

    Sun Hur

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Nature Reviews Molecular Cell Biology thanks Y. Modis, who co-refereed with A. Herrero del Valle, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Type I interferons

A large subgroup of secreted proteins that bind to interferon receptors and stimulate the expression of antiviral genes.

Caspase activation and recruitment domains

(CARDs). Interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis.

Pathogen-associated molecular patterns

(PAMPs). Conserved motifs that are associated with pathogen infection that serve as ligands for host pattern recognition receptors.

Stress granules

Molecular condensates that form in response to various cellular stresses. They often result from accumulation of stalled translation initiation complexes that expose mRNAs.

2′-5′-linked oligomers of adenosines

The polymerized form of ATP with the general formula pppA(2′p5′A)n that is catalysed by 2′-5′-oligoadenylate synthase. The oligomers activate ribonuclease L (RNase L), which mediates RNA degradation.

Ribonuclease L

(RNase L). An interferon-induced endoribonuclease that degrades RNA when activated.

Cyclic GMP–AMP synthase

(cGAS). A cytosolic DNA sensor that activates a type I interferon response, part of the cGAS–STING DNA sensing pathway.

Inflammasome

A multiprotein complex that forms in response to a variety of inflammatory triggers (both pathogen derived and host derived). Assembly of the inflammasome often leads to activation of caspase 1, which then processes inflammatory cytokines into their mature forms and induces gasdermin pore formation.

Gasdermin D

A member of the gasdermin family, which form pores in response to inflammasome activation. Gasdermin D pore formation leads to release of inflammatory cytokines and causes a highly inflammatory form of programmed cell death known as pyroptosis

Transposable elements

(TEs). DNA sequences that can change their position within a genome, sometimes creating or reversing mutations and altering the cell’s genetic identity and genome size.

Endogenous retroviruses

(ERVs). Endogenous viral elements in the genome that closely resemble and can be derived from retroviruses. These elements constitute up to 8% of the human genome.

Long interspersed nuclear elements

(LINEs). A group of retrotransposons that are not long terminal repeats. LINEs constitute ~21% of the human genome. They are transcribed into mRNA and translated into a protein that acts as a reverse transcriptase, which makes a DNA copy of the LINE RNA, which then can be integrated into the genome at a new site.

Short interspersed nuclear elements

Non-autonomous, non-coding retrotransposons that are capable of copying and pasting themselves into another region of the genome via an RNA intermediate and the action of reverse transcriptase. They constitute ~15% of the human genome.

Alu repeats

A clustered arrangement of Alu (a kind of short interspersed nuclear element), which can often be transcribed within a single transcript.

Circular RNAs

(circRNAs). Single-stranded RNAs where the 5′ and 3′ ends are joined through a phosphodiester bond.

MYC

A family of regulatory genes and proto-oncogenes that code for transcription factors. Many types of cancers have dysregulated MYC levels and activity.

Anti-J2 enrichment

Use of the anti-double-stranded RNA (dsRNA) J2 antibody to capture dsRNAs that are longer than 40 bp.

Nonsense-mediated decay

An evolutionarily conserved mechanism of degradation of mRNA species with a premature termination codon.

Systemic lupus erythematosus

(SLE). An autoimmune disease that causes widespread inflammation and tissue damage in the affected organs. It can affect the joints, skin, brain, lungs, kidneys and blood vessels.

Peripheral blood mononuclear cells

Any peripheral blood cell having a round nucleus, which includes lymphocytes and monocytes.

Dicer

An endoribonuclease specialized in processing double-stranded RNA. It is typically involved in biogenesis of small regulatory RNAs such as microRNAs and small interfering RNAs.

Pseudogenes

DNA sequences that resemble functional genes, but are inactive due to mutations.

RNA exosome

A multisubunit protein complex that catalyses 3′-to-5′ processing or degradation of cellular RNAs

Trichohepatoenteric syndrome

An inherited autosomal recessive condition that affects the hair, liver and intestines. Can be caused by mutations in SKIV2L or TTC37.

Signal recognition particle (SRP) ribonucleoprotein complex

A ribonucleoprotein complex that recognizes the signal sequence of a nascent peptide and targets it to the endoplasmic reticulum in eukaryotes and the plasma membrane in prokaryotes.

Cell cycle checkpoint

A checkpoint in the eukaryotic cell cycle at which the cell monitors the progression of cell division and decides whether or not to move forward.

Unfolded protein response

An evolutionarily conserved adaptive reaction that reduces unfolded protein load to maintain cell viability and function. Depending on the cell type involved and the nature of the stress stimuli, unfolded protein response signalling has different consequences and kinetics.

Integrated stress response

An evolutionarily conserved cellular stress response that downregulates protein synthesis and upregulates specific genes in response to internal or environmental stresses.

JNK

JUN N-terminal kinase (JNK) that plays key roles in many cellular stress and inflammatory signalling pathways.

Aicardi–Goutières syndrome

An inherited encephalopathy that affects newborns and usually results in severe mental and physical handicap. It can be caused by gain-of-function mutations in IFIH1 (the gene encoding MDA5). Loss-of-function mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1 and ADAR1 were also shown to cause Aicardi–Goutières syndrome.

Singleton–Merten syndrome

A rare autoimmune disorder characterized by tooth abnormalities, calcifications in the aorta and certain valves of the heart, and osteoporosis in the hands and feet. It can be caused by a gain-of-function mutation in IFIH1 (the gene encoding MDA5) or DDX58 (the gene encoding RIG-I).

Single-nucleotide polymorphisms

Germline substitutions of a single nucleotide at a specific position in the genome, the most common type of genetic variation among people.

Vitiligo

An autoimmune disease where the immune system attacks the melanocytes in the skin.

Psoriasis

An autoimmune disease that speeds up the growth cycle of skin cells and causes red, itchy scaly patches over the body.

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Chen, Y.G., Hur, S. Cellular origins of dsRNA, their recognition and consequences. Nat Rev Mol Cell Biol 23, 286–301 (2022). https://doi.org/10.1038/s41580-021-00430-1

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