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Review
. 2024 Jan 4;84(1):107-119.
doi: 10.1016/j.molcel.2023.11.033. Epub 2023 Dec 19.

The competitive landscape of the dsRNA world

Kyle A Cottrell  1 , Ryan J Andrews  2 , Brenda L Bass  3
Affiliations
Review

The competitive landscape of the dsRNA world

Kyle A Cottrell et al. Mol Cell. .

Abstract

The ability to sense and respond to infection is essential for life. Viral infection produces double-stranded RNAs (dsRNAs) that are sensed by proteins that recognize the structure of dsRNA. This structure-based recognition of viral dsRNA allows dsRNA sensors to recognize infection by many viruses, but it comes at a cost-the dsRNA sensors cannot always distinguish between "self" and "nonself" dsRNAs. "Self" RNAs often contain dsRNA regions, and not surprisingly, mechanisms have evolved to prevent aberrant activation of dsRNA sensors by "self" RNA. Here, we review current knowledge about the life of endogenous dsRNAs in mammals-the biosynthesis and processing of dsRNAs, the proteins they encounter, and their ultimate degradation. We highlight mechanisms that evolved to prevent aberrant dsRNA sensor activation and the importance of competition in the regulation of dsRNA sensors and other dsRNA-binding proteins.

Keywords: ADAR; DHX9; MDA5; PKR; RIG-I; antiviral; dsRNA-binding proteins; innate immunity; interferon.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. Open-reading frame structures and subcellular locations of dsRBPs.
Domain arrangements of human dsRBPs and RLRs are depicted as colored boxes (in legend) along the length of the peptide chain (gray). Lengths and domain architectures approximately to scale. Adjacent to each schematic is the subcellular location(s) for each: N for nuclear, C for cytoplasmic, M for mitochondrial, and S for nuclear speckles. All annotations were retrieved from the UniProt database on October 13th, 2023; we note that nuclear-cytoplasmic shuttling is pervasive, and it is difficult to prove exclusivity to a subcellular compartment.
Figure 2:
Figure 2:. A model for regulation by competition.
A) Balance between dsRNA sensors and dsRBPs. In a healthy cell (left), dsRNA sensors are expressed at low levels, but dsRBPs are prevalent and act to keep dsRNA sensors from being activated by dsRNA. dsRBPs can use different mechanisms to reduce the amount of immunogenic dsRNA available for interacting with dsRNA sensors, for example, they might edit, degrade or simply bind dsRNA. Upon loss of these dsRBPs (top right), or during a viral infection (bottom right) the concentration of dsRNA reaches a threshold that allows for dsRNA sensor activation. NLRP1, NLR family pyrin domain containing 1. B) Productive vs. nonproductive binding. Two dsRBPs are shown, each with two dsRBDs (blue) and a functional/catalytic domain (salmon). Productive binding involves each protein interacting with a single dsRNA; in one example the functional/catalytic domain also interacts with dsRNA, as would occur with an ADAR. In nonproductive binding a high concentration of dsRNA promotes dsRBD binding to different dsRNAs to form foci or clusters. C) Competitive binding dynamics. Two distinct dsRBPs, each with two dsRBDs (blue) and a single functional domain (dsRBP-1:salmon rectangle; dsRBP-2: green triangle), are first illustrated productively binding a single dsRNA. Next, dsRBP-2, with the help of accessory proteins (bottom) that confer a competitive edge (pink three-quarter circle), or increased concentration (top), displaces dsRBP-1, showcasing potential regulation of dsRBP functions through competition.
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