Mechanism mediated by a noncoding RNA, nc886, in the cytotoxicity of a DNA-reactive compound

et al. 2020

Preprint

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Protein kinase R (PKR) is an immune response protein that becomes activated by long doublestranded RNAs (dsRNAs). Several studies reported the misactivation of PKR in patients of degenerative diseases including primary osteoarthritis (OA). However, the molecular identity of PKR-activating dsRNAs remains unknown. Here, we investigate the role of mitochondrial dsRNAs (mt-dsRNAs) in the development of OA. We find that in response to OA-mimicking stressors, cytosolic efflux of mt-dsRNAs is increased, leading to PKR activation and subsequent induction of inflammatory cytokines and apoptosis. Moreover, mt-dsRNAs are exported to the extracellular space where they activate toll-like receptor 3. Elevated expression of mt-dsRNAs in the synovial fluids of OA patients further supports our data. Lastly, we show that autophagy protects chondrocytes from mitochondrial dysfunction partly by removing cytosolic mt-dsRNAs. Together, these findings establish the PKR-mt-dsRNA as a critical regulatory axis in OA development and suggest mt-dsRNAs as a potential target in fighting OA.

Section: Senescence-eliciting Stressors Also Induce Pkr Activation VImentioning

confidence: 91%

Mitochondrial dsRNAs activate PKR and TLR3 to promote chondrocyte degeneration in osteoarthritis

Kim

et al. 2020

Preprint

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“…Notwithstanding, few reports showed an oncogenic action of hsa-miR-886-3p in renal cell carcinoma [33], colorectal carcinoma [34] and esophageal squamous cell carcinoma [35]. A recent finding proposing a nc886/PKR loss mediated doxorubicin cytotoxicity raised a novel view about its specific contribution to chemotherapy response [36]. Overall, despite of the various reports assigning a microRNA function to hsa-miR-886-3p, its production as a specific nc886 processed product, its dependence on DICER and its association to Argonaute proteins has not been consistently demonstrated.The aim of this study was to investigate the production of small RNAs with microRNA-like function from nc886, and the biological effect and clinical significance of this small RNAs in prostate cancer.…”

mentioning

confidence: 99%

vtRNA2-1/nc886 Produces a Small RNA That Contributes to Its Tumor Suppression Action through the microRNA Pathway in Prostate Cancer

Fort

Garat

Sotelo‐Silveira

et al. 2020

ncRNA

vtRNA2-1 is a vault RNA initially classified as microRNA precursor hsa-mir-886 and recently proposed as “nc886”, a new type of non-coding RNA involved in cancer progression acting as an oncogene and tumor suppressor gene in different tissues. We have shown that vtRNA2-1/nc886 is epigenetically repressed in neoplastic cells, increasing cell proliferation and invasion in prostate tissue. Here we investigate the ability of vtRNA2-1/nc886 to produce small-RNAs and their biological effect in prostate cells. The interrogation of public small-RNA transcriptomes of prostate and other tissues uncovered two small RNAs, snc886-3p and snc886-5p, derived from vtRNA2-1/nc886 (previously hsa-miR-886-3p and hsa-miR-886-5p). Re-analysis of PAR-CLIP and knockout of microRNA biogenesis enzymes data showed that these small RNAs are products of DICER, independent of DROSHA, and associate with Argonaute proteins, satisfying microRNA attributes. In addition, the overexpression of snc886-3p provokes the downregulation of mRNAs bearing sequences complementary to its “seed” in their 3′-UTRs. Microarray and in vitro functional assays in DU145, LNCaP and PC3 cell lines revealed that snc886-3p reduced cell cycle progression and increases apoptosis, like its precursor vtRNA2-1/nc886. Finally, we found a list of direct candidate targets genes of snc886-3p upregulated and associated with disease condition and progression in PRAD-TCGA data. Overall, our findings suggest that vtRNA2-1/nc886 and its processed product snc886-3p are synthesized in prostate cells, exerting a tumor suppressor action.

“…“anti-nc886” and “anti-control” in the text and figures indicate “anti886 75_56” and “anti_vt 21_2”, respectively, in the reference. siRNAs directed against PKR and control were Stealth RNAi™ siRNA (Invitrogen), as described in [ 34 ]. Poly(I:C)-HMW(1.5–8 kb) and Poly(I:C)-LMW (0.2–1 kb) were purchased from Invivogen (San Diego, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Nc886, a Novel Suppressor of the Type I Interferon Response Upon Pathogen Intrusion

Bao

et al. 2021

IJMS

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Interferons (IFNs) are a crucial component in the innate immune response. Especially the IFN-β signaling operates in most cell types and plays a key role in the first line of defense upon pathogen intrusion. The induction of IFN-β should be tightly controlled, because its hyperactivation can lead to tissue damage or autoimmune diseases. Activation of the IFN-β promoter needs Interferon Regulatory Factor 3 (IRF3), together with Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Activator Protein 1 (AP-1). Here we report that a human noncoding RNA, nc886, is a novel suppressor for the IFN-β signaling and inflammation. Upon treatment with several pathogen-associated molecular patterns and viruses, nc886 suppresses the activation of IRF3 and also inhibits NF-κB and AP-1 via inhibiting Protein Kinase R (PKR). These events lead to decreased expression of IFN-β and resultantly IFN-stimulated genes. nc886′s role might be to restrict the IFN-β signaling from hyperactivation. Since nc886 expression is regulated by epigenetic and environmental factors, nc886 might explain why innate immune responses to pathogens are variable depending on biological settings.