Long double-stranded RNA may undergo hyper-editing by adenosine deaminases that act on RNA (ADARs), where up to 50% of adenosine residues may be converted to inosine. However, although numerous RNAs may undergo hyper-editing, the role for inosine-containing hyper-edited double-stranded RNA in cells is poorly understood. Nevertheless, editing plays a critical role in mammalian cells, as highlighted by the analysis of ADAR-null mutants. In particular, the long form of ADAR1 (ADAR1p150) is essential for viability. Moreover, a number of studies have implicated ADAR1p150 in various stress pathways. We have previously shown that ADAR1p150 localized to cytoplasmic stress granules in HeLa cells following either oxidative or interferon-induced stress. Here, we show that the Z-DNA-binding domain (ZαADAR1) exclusively found in ADAR1p150 is required for its localization to stress granules. Moreover, we show that fusion of ZαADAR1 to either green fluorescent protein (GFP) or polypyrimidine binding protein 4 (PTB4) also results in their localization to stress granules. We additionally show that the Zα domain from other Z-DNA-binding proteins (ZBP1, E3L) is likewise sufficient for localization to stress granules. Finally, we show that Z-RNA or Z-DNA binding is important for stress granule localization. We have thus identified a novel role for Z-DNA-binding domains in mammalian cells.
Interferon regulatory factor 9 (IRF9) is an integral transcription factor in mediating the type I interferon antiviral response, as part of the interferon-stimulated gene factor 3. However, the role of IRF9 in many important non-communicable diseases has just begun to emerge. The duality of IRF9’s role in conferring protection but at the same time exacerbates diseases is certainly puzzling. The regulation of IRF9 during these conditions is not well understood. The high homology of IRF9 DNA-binding domain to other IRFs, as well as the recently resolved IRF9 IRF-associated domain structure can provide the necessary insights for progressive inroads on understanding the regulatory mechanism of IRF9. This review sought to outline the structural basis of IRF9 that guides its regulation and interaction in antiviral immunity and other diseases.
There is emerging evidence that hydrogen-rich water (H2-water) has beneficial effects on the physiological responses to exercise. However, few studies investigate its ergogenic potential. This randomized controlled trial examined the effects of H2-water ingestion on physiological responses and exercise performance during incremental treadmill running. In a double-blind crossover design, 14 endurance-trained male runners (age, 34 ± 4 years; body mass, 63.1 ± 7.2 kg; height, 1.72 ± 0.05 m) were randomly assigned to ingest 2 doses of 290-mL H2-water or placebo on each occasion. The first bolus was given before six 4-min submaximal running bouts, and the second bolus was consumed before the maximal incremental running test. Expired gas, heart rate (HR), and ratings of perceived exertion (RPE) were recorded; blood samples were collected at the end of each submaximal stage and post maximal running test. Cardiorespiratory responses, RPE, and blood gas indices were not significantly different at each submaximal running intensity (range: 34%–91% maximal oxygen uptake) between H2-water and placebo trials. No statistical difference was observed in running time to exhaustion (618 ± 126 vs. 619 ± 113 s), maximal oxygen uptake (56.9 ± 4.4 vs. 57.1 ± 4.7 mL·kg−1·min−1), maximal HR (184 ± 7 vs. 184 ± 7 beat·min−1), and RPE (19 ± 1 vs. 19 ± 1) in the runners between the trials. The results suggest that the ingestion of 290 mL of H2-water before submaximal treadmill running and an additional dose before the subsequent incremental running to exhaustion were not sufficiently ergogenic in endurance-trained athletes. Novelty Acute ingestion of H2-water does not seem to be ergogenic for endurance performance. A small dose of H2-water does not modulate buffering capacity during intense endurance exercise in athletes.
Both DNA and RNA can maintain left-handed double helical Z-conformation under physiological condition, but only when stabilized by Z-DNA binding domain (ZDBD). After initial discovery in RNA editing enzyme ADAR1, ZDBD has also been described in pathogen-sensing proteins ZBP1 and PKZ in host, as well as virulence proteins E3L and ORF112 in viruses. The host-virus antagonism immediately highlights the importance of ZDBD in antiviral innate immunity. Furthermore, Z-RNA binding has been shown to be responsible for the localization of these ZDBD-containing proteins to cytoplasmic stress granules that play central role in coordinating cellular response to stresses. This review sought to consolidate current understanding of Z-RNA sensing in innate immunity and implore possible roles of Z-RNA binding within cytoplasmic stress granules.
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