ADAR and hnRNPC deficiency synergize in activating endogenous dsRNA-induced type I IFN responses.
Abstract
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.
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Linked Datasets (1)
RNAseq of hnRNPC and ADAR deficient THP-1
Homo sapiens66 data files
| File | Type | Size |
|---|---|---|
| LIB1114296_SAM24343681_R1.fastq.gz | RNA-Seq | 10.2 GB |
| LIB1114297_SAM24343682_R1.fastq.gz | RNA-Seq | 10.9 GB |
| LIB1114298_SAM24343683_R1.fastq.gz | RNA-Seq | 11.1 GB |
| LIB1114299_SAM24343684_R1.fastq.gz | RNA-Seq | 10.4 GB |
| LIB1114300_SAM24343685_R1.fastq.gz | RNA-Seq | 14.3 GB |
| LIB1114301_SAM24343686_R1.fastq.gz | RNA-Seq | 13.8 GB |
| LIB1114302_SAM24343687_R1.fastq.gz | RNA-Seq | 12.3 GB |
| LIB1114303_SAM24343688_R1.fastq.gz | RNA-Seq | 13.3 GB |
| LIB1114304_SAM24343689_R1.fastq.gz | RNA-Seq | 13.9 GB |
| LIB1114305_SAM24343690_R1.fastq.gz | RNA-Seq | 12.4 GB |
| LIB1114306_SAM24343691_R1.fastq.gz | RNA-Seq | 13.0 GB |
| LIB1114307_SAM24343692_R1.fastq.gz | RNA-Seq | 12.2 GB |
| LIB1114308_SAM24343693_R1.fastq.gz | RNA-Seq | 12.5 GB |
| LIB1114309_SAM24343694_R1.fastq.gz | RNA-Seq | 13.9 GB |
| LIB1114310_SAM24343695_R1.fastq.gz | RNA-Seq | 14.4 GB |
| LIB1114311_SAM24343696_R1.fastq.gz | RNA-Seq | 14.0 GB |
| LIB1114312_SAM24343697_R1.fastq.gz | RNA-Seq | 14.2 GB |
| LIB1114313_SAM24343698_R1.fastq.gz | RNA-Seq | 13.0 GB |
| LIB1114323_SAM24343708_R1.fastq.gz | RNA-Seq | 10.2 GB |
| LIB1114324_SAM24343709_R1.fastq.gz | RNA-Seq | 10.5 GB |
| LIB1114325_SAM24343710_R1.fastq.gz | RNA-Seq | 10.7 GB |
| LIB1114326_SAM24343711_R1.fastq.gz | RNA-Seq | 11.2 GB |
| LIB1114327_SAM24343712_R1.fastq.gz | RNA-Seq | 11.2 GB |
| LIB1114328_SAM24343713_R1.fastq.gz | RNA-Seq | 11.5 GB |
| LIB1114329_SAM24343714_R1.fastq.gz | RNA-Seq | 10.2 GB |
| LIB1114330_SAM24343715_R1.fastq.gz | RNA-Seq | 9.5 GB |
| LIB1114331_SAM24343716_R1.fastq.gz | RNA-Seq | 10.3 GB |
| LIB1114332_SAM24343717_R1.fastq.gz | RNA-Seq | 11.1 GB |
| LIB1114333_SAM24343718_R1.fastq.gz | RNA-Seq | 11.7 GB |
| LIB1114334_SAM24343719_R1.fastq.gz | RNA-Seq | 11.4 GB |
| LIB1114335_SAM24343720_R1.fastq.gz | RNA-Seq | 10.4 GB |
| LIB1114336_SAM24343721_R1.fastq.gz | RNA-Seq | 10.7 GB |
| LIB1114337_SAM24343722_R1.fastq.gz | RNA-Seq | 11.1 GB |
| LIB1114338_SAM24343723_R1.fastq.gz | RNA-Seq | 10.0 GB |
| LIB1114339_SAM24343724_R1.fastq.gz | RNA-Seq | 11.3 GB |
| LIB1114340_SAM24343725_R1.fastq.gz | RNA-Seq | 11.5 GB |
| LIB1114359_SAM24343744_R1.fastq.gz | RNA-Seq | 11.2 GB |
| LIB1114360_SAM24343745_R1.fastq.gz | RNA-Seq | 10.5 GB |
| LIB1114361_SAM24343746_R1.fastq.gz | RNA-Seq | 10.5 GB |
| LIB1114362_SAM24343747_R1.fastq.gz | RNA-Seq | 9.3 GB |
| LIB1114363_SAM24343748_R1.fastq.gz | RNA-Seq | 11.1 GB |
| LIB1114364_SAM24343749_R1.fastq.gz | RNA-Seq | 11.9 GB |
| LIB1114365_SAM24343750_R1.fastq.gz | RNA-Seq | 10.7 GB |
| LIB1114366_SAM24343751_R1.fastq.gz | RNA-Seq | 10.5 GB |
| LIB1114367_SAM24343752_R1.fastq.gz | RNA-Seq | 10.1 GB |
| LIB1114368_SAM24343753_R1.fastq.gz | RNA-Seq | 10.3 GB |
| LIB1114369_SAM24343754_R1.fastq.gz | RNA-Seq | 10.6 GB |
| LIB1114370_SAM24343755_R1.fastq.gz | RNA-Seq | 12.3 GB |
| LIB5420086_SAM24363862_R1.fastq.gz | RNA-Seq | 9.6 GB |
| LIB5420087_SAM24363863_R1.fastq.gz | RNA-Seq | 8.7 GB |
| LIB5420088_SAM24363864_R1.fastq.gz | RNA-Seq | 9.4 GB |
| LIB5420089_SAM24363865_R1.fastq.gz | RNA-Seq | 10.7 GB |
| LIB5420090_SAM24363866_R1.fastq.gz | RNA-Seq | 10.1 GB |
| LIB5420091_SAM24363867_R1.fastq.gz | RNA-Seq | 8.5 GB |
| LIB5420092_SAM24363868_R1.fastq.gz | RNA-Seq | 7.9 GB |
| LIB5420093_SAM24363869_R1.fastq.gz | RNA-Seq | 7.8 GB |
| LIB5420094_SAM24363870_R1.fastq.gz | RNA-Seq | 9.6 GB |
| LIB5420095_SAM24363871_R1.fastq.gz | RNA-Seq | 8.3 GB |
| LIB5420096_SAM24363872_R1.fastq.gz | RNA-Seq | 8.6 GB |
| LIB5420097_SAM24363873_R1.fastq.gz | RNA-Seq | 9.4 GB |
| LIB5420098_SAM24363874_R1.fastq.gz | RNA-Seq | 8.8 GB |
| LIB5420099_SAM24363875_R1.fastq.gz | RNA-Seq | 7.9 GB |
| LIB5420100_SAM24363876_R1.fastq.gz | RNA-Seq | 7.8 GB |
| LIB5420101_SAM24363877_R1.fastq.gz | RNA-Seq | 9.1 GB |
| LIB5420102_SAM24363878_R1.fastq.gz | RNA-Seq | 9.2 GB |
| LIB5420103_SAM24363879_R1.fastq.gz | RNA-Seq | 8.3 GB |
Potentially Related Datasets (1)
These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.