The RNA-Editing Enzyme ADAR1 Controls Innate Immune Responses to RNA

The ADAR RNA-editing enzymes deaminate adenosine bases to inosines in cellular RNAs. Aberrant interferon expression occurs in patients in whom ADAR1 mutations cause Aicardi-Goutières syndrome (AGS) or dystonia arising from striatal neurodegeneration. Adar1 mutant mouse embryos show aberrant interferon induction and die by embryonic day E12.5. We demonstrate that Adar1 embryonic lethality is rescued to live birth in Adar1; Mavs double mutants in which the antiviral interferon induction response to cytoplasmic double-stranded RNA (dsRNA) is prevented. Aberrant immune responses in Adar1 mutant mouse embryo fibroblasts are dramatically reduced by restoring the expression of editing-active cytoplasmic ADARs. We propose that inosine in cellular RNA inhibits antiviral inflammatory and interferon responses by altering RLR interactions. Transfecting dsRNA oligonucleotides containing inosine-uracil base pairs into Adar1 mutant mouse embryo fibroblasts reduces the aberrant innate immune response. ADAR1 mutations causing AGS affect the activity of the interferon-inducible cytoplasmic isoform more severely than the nuclear isoform

Successful treatment of residual pituitary adenoma in persistent acromegaly following localisation by 11C-methionine PET co-registered with MRI.

OBJECTIVE: To determine if functional imaging using 11C-methionine positron emission tomography co-registered with 3D gradient echo MRI (Met-PET/MRI), can identify sites of residual active tumour in treated acromegaly, and discriminate these from post-treatment change, to allow further targeted treatment. DESIGN/METHODS: Twenty-six patients with persistent acromegaly after previous treatment, in whom MRI appearances were considered indeterminate, were referred to our centre for further evaluation over a 4.5-year period. Met-PET/MRI was performed in each case, and findings were used to decide regarding adjunctive therapy. Four patients with clinical and biochemical remission after transsphenoidal surgery (TSS), but in whom residual tumour was suspected on post-operative MRI, were also studied. RESULTS: Met-PET/MRI demonstrated tracer uptake only within the normal gland in the four patients who had achieved complete remission after primary surgery. In contrast, in 26 patients with active acromegaly, Met-PET/MRI localised sites of abnormal tracer uptake in all but one case. Based on these findings, fourteen subjects underwent endoscopic TSS, leading to a marked improvement in (n = 7), or complete resolution of (n = 7), residual acromegaly. One patient received stereotactic radiosurgery and two patients with cavernous sinus invasion were treated with image-guided fractionated radiotherapy, with good disease control. Three subjects await further intervention. Five patients chose to receive adjunctive medical therapy. Only one patient developed additional pituitary deficits after Met-PET/MRI-guided TSS. CONCLUSIONS: In patients with persistent acromegaly after primary therapy, Met-PET/MRI can help identify the site(s) of residual pituitary adenoma when MRI appearances are inconclusive and direct further targeted intervention (surgery or radiotherapy).This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. OK, ASP, NB, JDP and MG are supported by the NIHR Cambridge Biomedical Research Centre. JDP has received support by an NIHR Senior Investigator award and NIHR brain injury HTC.This is the author accepted manuscript. The final version is available from BioScientifica via https://doi.org/10.1530/EJE-16-063

A schematic representation of the ADAR and related ADAD proteins present in humans.

<p>All proteins have dsRNA binding domains (grey box) and a C-terminal deaminase domain (purple box). A nuclear localization sequence (NLS) is marked in red, whereas the nuclear export signal (NES) present in ADAR1 is marked in green. Z-DNA binding domains are indicated by an orange box in ADAR1. A region enriched in arginine/lysine residues, R domain is present in ADAR3 (blue box). The number of amino acids is indicated on the right.</p

A model for the role of ADAR1 in innate immunity.

<p>(A) DsRNA that is generated during transcription is edited by ADARs. The dsRNA contain inosine that can bind to the RLRs, MDA5 and RIG-I, in the cytoplasm and inhibit their activation. (B) During a viral infection, or if ADAR1 is inactive, unedited dsRNA is present in the cytoplasm. This dsRNA binds to MDA5 and RIG-I, activating MAVS which, in turn, leads to the phosphorylation of IRF3 and its translocation into the nucleus and induces the type 1 interferon response. (C) The ADAR1 isoform p150 is induced by interferon late in the response. This isoform is predominantly cytoplasmic and it edits all dsRNA either of viral or cellular origin. This generates inosine containing dsRNA that can inhibit the RLR receptors, thus turning off the interferon response as the transcription factor IRF9 is unable to continue to transcribe the ISGs.</p

The Histone Demethylase KDM4A Is Required to Sustain H3K9me3/H3K27me3 Epigenetic States and Oncogenesis in MLL-AF9 Acute Myeloid Leukemia

No abstract available

The Histone Demethylase KDM4A Is Required to Sustain H3K9me3/H3K27me3 Epigenetic States and Oncogenesis in MLL-AF9 Acute Myeloid Leukemia

No abstract available

Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature

Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutières syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements