Circulating microbial small RNAs are altered in patients with rheumatoid arthritis.

OBJECTIVES: To determine if plasma microbial small RNAs (sRNAs) are altered in patients with rheumatoid arthritis (RA) compared with control subjects, associated with RA disease-related features, and altered by disease-modifying antirheumatic drugs (DMARDs). METHODS: sRNA sequencing was performed on plasma from 165 patients with RA and 90 matched controls and a separate cohort of 70 patients with RA before and after starting a DMARD. Genome alignments for RA-associated bacteria, representative bacterial and fungal human microbiome genomes and environmental bacteria were performed. Microbial genome counts and individual sRNAs were compared across groups and correlated with disease features. False discovery rate was set at 0.05. RESULTS: Genome counts of Lactobacillus salivarius, Anaerobaculum hydrogeniformans, Staphylococcus epidermidis, Staphylococcus aureus, Paenisporosarcina spp, Facklamia hominis, Sphingobacterium spiritivorum, Lentibacillus amyloliquefaciens, Geobacillus spp, and Pseudomonas fluorescens were significantly decreased in the plasma of RA compared with control subjects. Three microbial transfer RNA-derived sRNAs were increased in RA versus controls and inversely associated with disease activity. Higher total microbial sRNA reads were associated with lower disease activity in RA. Baseline total microbial sRNAs were threefold higher among patients who improved with DMARD versus those who did not but did not change significantly after 6 months of treatment. CONCLUSION: Plasma microbial sRNA composition is altered in RA versus control subjects and associated with some measures of RA disease activity. DMARD treatment does not alter microbial sRNA abundance or composition, but increased abundance of microbial sRNAs at baseline was associated with disease activity improvement at 6 months.

Identification of tRFs and phasiRNAs in tomato (Solanum lycopersicum) and their responses to exogenous abscisic acid.

BACKGROUND: The non-coding small RNA tRFs (tRNA-derived fragments) and phasiRNAs (plant-specific) exert important roles in plant growth, development and stress resistances. However, whether the tRFs and phasiRNAs respond to the plant important stress hormone abscisic acid (ABA) remain enigma. RESULTS: Here, the RNA-sequencing was implemented to decipher the landscape of tRFs and phasiRNAs in tomato (Solanum lycopersicum) leaves and their responses when foliar spraying exogenous ABA after 24 h. In total, 733 tRFs and 137 phasiRNAs were detected. The tRFs were mainly derived from the tRNAAla transporting alanine, which tended to be cleaved at the 5'terminal guanine site and D loop uracil site to produce tRFAla with length of 20 nt. Most of phasiRNAs originated from NBS-LRR resistance genes. Expression analysis revealed that 156 tRFs and 68 phasiRNAs expressed differentially, respectively. Generally, exogenous ABA mainly inhibited the expression of tRFs and phasiRNAs. Furthermore, integrating analysis of target gene prediction and transcriptome data presented that ABA significantly downregulated the abundance of phsaiRNAs associated with biological and abiotic resistances. Correspondingly, their target genes such as AP2/ERF, WRKY and NBS-LRR, STK and RLK, were mainly up-regulated. CONCLUSIONS: Combined with the previous analysis of ABA-response miRNAs, it was speculated that ABA can improve the plant resistances to various stresses by regulating the expression and interaction of small RNAs (such as miRNAs, tRFs, phasiRNAs) and their target genes. This study enriches the plant tRFs and phasiRNAs, providing a vital basis for further investigating ABA response-tRFs and phasiRNAs and their functions in biotic and abiotic stresses.

A small RNA decreases the sensitivity of Shigella sonnei to norfloxacin.

OBJECTIVES: Shigella is a human pathogen that causes shigellosis, an acute invasive intestinal infection. Recent studies in the model bacterium Escherichia coli (E. coli) provided evidence that small regulatory RNAs (sRNAs) can contribute to antimicrobial resistance or susceptibility. One of the sRNAs is SdsR, which increases sensitivity of E. coli against fluoroquinolone by repressing the drug efflux pump, TolC. However, no reports exist about the effect of SdsR on fluoroquinolone resistance in Shigella sonnei (S. sonnei). In this study, we established the effect of SdsR on the sensitivity of S. sonnei to norfloxacin. DATA DESCRIPTION: We tested the effects of SdsR and SdsRv2 on fluoroquinolone resistance in S. sonnei in vivo. SdsRv2 is a synthetic version which promotes higher binding stability to tolC mRNA. Overexpression of either SdsR or SdsRv2 lowers the expression of tolC mRNA. Interestingly, SdsR and SdsRv2 promote the growth of S. sonnei in the presence of a sub-inhibitory concentration of norfloxacin. Mutant carrying SdsRv2 showed the highest growth advantage. This phenotype is opposite to the effect of SdsR reported in E. coli. This study is an example that demonstrates the difference in the phenotypic effect of a highly conserved sRNA in two closely related bacteria.

Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs.

Emerging evidence indicates that ionizing radiation (IR) and chemotherapy activate Type I interferon (IFN) signaling in tumor and host cells. However, the mechanism of induction is poorly understood. We identified a novel radioprotective role for the DEXH box RNA helicase LGP2 (DHX58) through its suppression of IR-induced cytotoxic IFN-beta [1]. LGP2 inhibits activation of the RIG-I-like receptor (RLR) pathway upon binding of viral RNA to the cytoplasmic sensors RIG-I (DDX58) and MDA5 (IFIH1) and subsequent IFN signaling via the mitochondrial adaptor protein MAVS (IPS1). Here we show that MAVS is necessary for IFN-beta induction and interferon-stimulated gene expression in the response to IR. Suppression of MAVS conferred radioresistance in normal and cancer cells. Germline deletion of RIG-I, but not MDA5, protected mice from death following total body irradiation, while deletion of LGP2 accelerated the death of irradiated animals. In human tumors depletion of RIG-I conferred resistance to IR and different classes of chemotherapy drugs. Mechanistically, IR stimulated the binding of cytoplasmic RIG-I with small endogenous non-coding RNAs (sncRNAs), which triggered IFN-beta activity. We demonstrate that the small nuclear RNAs U1 and U2 translocate to the cytoplasm after IR treatment, thus stimulating the formation of RIG-I: RNA complexes and initiating downstream signaling events. Taken together, these findings suggest that the physiologic responses to radio-/chemo-therapy converge on an antiviral program in recruitment of the RLR pathway by a sncRNA-dependent activation of RIG-I which commences cytotoxic IFN signaling. Importantly, activation of interferon genes by radiation or chemotherapy is associated with a favorable outcome in patients undergoing treatment for cancer. To our knowledge, this is the first demonstration of a cell-intrinsic response to clinically relevant genotoxic treatments mediated by an RNA-dependent mechanism.