scholarly journals ADAR and hnRNPC deficiency synergize in activating endogenous dsRNA-induced type I IFN responses

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
Anna-Maria Herzner ◽  
Zia Khan ◽  
Eric L. Van Nostrand ◽  
Sara Chan ◽  
Trinna Cuellar ◽  
...  
Keyword(s):  
Repetitive Element ◽  
Type I ◽  
Type I Ifn ◽  
Rna Seq ◽  
Splice Sites ◽  
Double Stranded Rna ◽  
Alu Elements ◽  
Synergistic Induction ◽  
Plausible Mechanism ◽  
Cryptic Splice Sites

Cytosolic double-stranded RNA (dsRNA) initiates type I IFN responses. Endogenous retroelements, notably Alu elements, constitute a source of dsRNA. Adenosine-to-inosine (A-to-I) editing by ADAR induces mismatches in dsRNA and prevents recognition by MDA5 and autoinflammation. To identify additional endogenous dsRNA checkpoints, we conducted a candidate screen in THP-1 monocytes and found that hnRNPC and ADAR deficiency resulted in synergistic induction of MDA5-dependent IFN responses. RNA-seq analysis demonstrated dysregulation of Alu-containing introns in hnRNPC-deficient cells via utilization of unmasked cryptic splice sites, including introns containing ADAR-dependent A-to-I editing clusters. These putative MDA5 ligands showed reduced editing in the absence of ADAR, providing a plausible mechanism for the combined effects of hnRNPC and ADAR. This study contributes to our understanding of the control of repetitive element–induced autoinflammation and suggests that patients with hnRNPC-mutated tumors might maximally benefit from ADAR inhibition-based immunotherapy.

scholarly journals Endogenous mitochondrial double‐stranded RNA is not an activator of the type I interferon response in human pancreatic beta cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alexandra Coomans de Brachène ◽  
Angela Castela ◽  
Anyïshai E. Musuaya ◽  
Lorella Marselli ◽  
Piero Marchetti ◽  
...  
Keyword(s):  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Viral Infections ◽  
Human Islets ◽  
Interferon Response ◽  
Interferon Α ◽  
Type I ◽  
Type I Ifn ◽  
Danger Signal ◽  
Double Stranded Rna

Abstract Background Type 1 diabetes (T1D) is an autoimmune disease characterized by the progressive destruction of pancreatic beta cells. Interferon-α (IFNα), an antiviral cytokine, is expressed in the pancreatic islets in early T1D, which may be secondary to viral infections. However, not all patients harboring a type I IFN signature present signals of viral infection, suggesting that this response might be initiated by other “danger signals”. Accumulation of mitochondrial double-stranded RNA (mtdsRNA; a danger signal), secondary to silencing of members of the mitochondrial degradosome, PNPT1 and SUV3, has been described to activate the innate immune response. Methods To evaluate whether mtdsRNA represents a “danger signal” for pancreatic beta cells in the context of T1D, we silenced PNPT1 and/or SUV3 in slowly proliferating human insulin-secreting EndoC-βH1 cells and in non-proliferating primary human beta cells and evaluated dsRNA accumulation by immunofluorescence and the type I IFN response by western blotting and RT-qPCR. Results Only the simultaneous silencing of PNPT1/SUV3 induced dsRNA accumulation in EndoC-βH1 cells but not in dispersed human islets, and there was no induction of a type I IFN response. By contrast, silencing of these two genes individually was enough to induce dsRNA accumulation in fibroblasts present in the human islet preparations. Conclusions These data suggest that accumulation of endogenous mtdsRNA following degradosome knockdown depends on the proliferative capacity of the cells and is not a mediator of the type I IFN response in human pancreatic beta cells.

scholarly journals Hypoxia regulates endogenous double-stranded RNA production via reduced mitochondrial DNA transcription

2020 ◽  
Author(s):  
Esther Arnaiz ◽  
Ana Miar ◽  
Antonio Gregorio Dias ◽  
Naveen Prasad ◽  
Ulrike Schulze ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Type I Interferon ◽  
Type I ◽  
Cancer Therapies ◽  
Common Phenomenon ◽  
Type I Ifn ◽  
Hallmarks Of Cancer ◽  
Mitochondrial Transcription ◽  
Double Stranded Rna ◽  
Local Immunosuppression

ABSTRACTHypoxia is a common phenomenon in solid tumours strongly linked to the hallmarks of cancer. Hypoxia promotes local immunosuppression and downregulates type I interferon (IFN) expression and signalling, which contribute to the success of many cancer therapies. Double-stranded RNA (dsRNA), transiently generated during mitochondrial transcription, endogenously activates the type I IFN pathway. We report the effects of hypoxia on the generation of mitochondrial dsRNA (mtdsRNA) in breast cancer. We found a significant decrease in dsRNA production in different cell lines under hypoxia. This was HIF1α/2α-independent. mtdsRNA was responsible for induction of type I IFN and significantly decreased after hypoxia. Mitochondrially encoded gene expression was downregulated and mtdsRNA bound by the dsRNA-specific J2 antibody was decreased during hypoxia. These findings reaveal a mechanism of hypoxia-induced immunosuppression that could be targeted by hypoxia-activated therapies.

scholarly journals Dendritic cells activated by double-stranded RNA induce arthritis via autocrine type I IFN signaling

2013 ◽  
Vol 95 (4) ◽  
pp. 661-666 ◽  
Author(s):  
S. C. Narendra ◽  
J. P. Chalise ◽  
N. Hook ◽  
M. Magnusson
Keyword(s):  
Dendritic Cells ◽  
Type I ◽  
Type I Ifn ◽  
Double Stranded Rna ◽  
Induce Arthritis

scholarly journals Analysis of the Immune Responses in the Ileum of Gnotobiotic Pigs Infected with the Recombinant GII.p12_GII.3 Human Norovirus by mRNA Sequencing

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 92
Author(s):  
Byung-Joo Park ◽  
Hee-Seop Ahn ◽  
Sang-Hoon Han ◽  
Hyeon-Jeong Go ◽  
Dong-Hwi Kim ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Type I ◽  
Type I Ifn ◽  
Rna Seq ◽  
Human Norovirus ◽  
Mrna Sequencing ◽  
Gnotobiotic Pigs

Norovirus genogroup II (NoV GII) induces acute gastrointestinal food-borne illness in humans. Because gnotobiotic pigs can be infected with human norovirus (HuNoV) GII, they are frequently used to analyze the associated pathogenic mechanisms and immune responses, which remain poorly understood. Recently, mRNA sequencing analysis (RNA-Seq) has been used to identify cellular responses to viruses. In this study, we investigated the host immune response and possible mechanisms involved in virus evasion in the ileum of gnotobiotic pigs infected with HuNoV by RNA-Seq. HuNoV was detected in the feces, blood, and tissues of the jejunum, ileum, colon, mesenteric lymph node, and spleen of pigs infected with HuNoV. In analysis of mRNA sequencing, expression of anti-viral protein genes such as OAS1, MX1, and MX2 were largely decreased, whereas type I IFN was increased in pigs infected with HuNoV. In addition, expression of TNF and associated anti-inflammatory cytokine genes such as IL10 was increased in HuNoV-infected pigs. Expression of genes related to natural killer (NK) cell cytotoxicity and CD8+ T cell exhaustion was increased, whereas that of MHC class I genes was decreased. Expression profiles of selected genes were further confirmed by qRT-PCR and Western blot. These results suggest that infection with HuNoV induces NK cell-mediated cytotoxicity but suppresses type I IFN- and CD8+ T cell-mediated antiviral responses.

scholarly journals Hypoxia Regulates Endogenous Double-Stranded RNA Production via Reduced Mitochondrial DNA Transcription

2021 ◽  
Vol 11 ◽  
Author(s):  
Esther Arnaiz ◽  
Ana Miar ◽  
Antonio Gregorio Dias Junior ◽  
Naveen Prasad ◽  
Ulrike Schulze ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Type I Interferon ◽  
Type I ◽  
Cancer Therapies ◽  
Common Phenomenon ◽  
Type I Ifn ◽  
Hallmarks Of Cancer ◽  
Mitochondrial Transcription ◽  
Double Stranded Rna ◽  
Local Immunosuppression

Hypoxia is a common phenomenon in solid tumours strongly linked to the hallmarks of cancer. Hypoxia promotes local immunosuppression and downregulates type I interferon (IFN) expression and signalling, which contribute to the success of many cancer therapies. Double-stranded RNA (dsRNA), transiently generated during mitochondrial transcription, endogenously activates the type I IFN pathway. We report the effects of hypoxia on the generation of mitochondrial dsRNA (mtdsRNA) in breast cancer. We found a significant decrease in dsRNA production in different cell lines under hypoxia. This effect was HIF1α/2α-independent. mtdsRNA was responsible for induction of type I IFN and significantly decreased after hypoxia. Mitochondrially encoded gene expression was downregulated and mtdsRNA bound by the dsRNA-specific J2 antibody was decreased during hypoxia. These findings reveal a new mechanism of hypoxia-induced immunosuppression that could be targeted by hypoxia-activated therapies.

scholarly journals Transcriptional Profiling of Human Peripheral Blood Mononuclear Cells Stimulated by Mycobacterium tuberculosis PPE57 Identifies Characteristic Genes Associated With Type I Interferon Signaling

2021 ◽  
Vol 11 ◽  
Author(s):  
Fanli Yi ◽  
Jing Hu ◽  
Xiaoyan Zhu ◽  
Yue Wang ◽  
Qiuju Yu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Glutamic Acid ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Type I ◽  
Type I Ifn ◽  
Rna Seq ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Proline-glutamic acid (PE)- and proline-proline-glutamic acid (PPE)-containing proteins are exclusive to Mycobacterium tuberculosis (MTB), the leading cause of tuberculosis (TB). In this study, we performed global transcriptome sequencing (RNA-Seq) on PPE57-stimulated peripheral blood mononuclear cells (PBMCs) and control samples to quantitatively measure the expression level of key transcripts of interest. A total of 1367 differentially expressed genes (DEGs) were observed in response to a 6 h exposure to PPE57, with 685 being up-regulated and 682 down-regulated. Immune-related gene functions and pathways associated with these genes were evaluated, revealing that the type I IFN signaling pathway was the most significantly enriched pathway in our RNA-seq dataset, with 14 DEGs identified therein including ISG15, MX2, IRF9, IFIT3, IFIT2, OAS3, IFIT1, IFI6, OAS2, OASL, RSAD2, OAS1, IRF7, and MX1. These PPE57-related transcriptomic profiles have implications for a better understanding of host global immune mechanisms underlying MTB infection outcomes. However, more studies regarding these DEGs and type I IFN signaling in this infectious context are necessary to more fully clarify the underlying mechanisms that arise in response to PPE57 during MTB infection.

scholarly journals Cell-Associated Double-Stranded RNA Enhances Antitumor Activity through the Production of Type I IFN

2006 ◽  
Vol 177 (9) ◽  
pp. 6122-6128 ◽  
Author(s):  
Sara McBride ◽  
Kasper Hoebe ◽  
Philippe Georgel ◽  
Edith Janssen
Keyword(s):  
Antitumor Activity ◽  
Type I ◽  
Type I Ifn ◽  
Double Stranded Rna
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