ADAR and hnRNPC deficiency synergize in activating endogenous dsRNA-induced type I IFN responses.
Anna-Maria Herzner, Zia Khan, Eric L Van Nostrand, Sara Chan, Trinna Cuellar, Ronald Chen, Ximo Pechuan-Jorge, Laszlo Komuves, Margaret Solon, Zora Modrusan, Benjamin Haley, Gene W Yeo, Timothy W Behrens, Matthew L Albert
The Journal of experimental medicine · 2021 · Vol. 218 (9)
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.
Linked datasets 1
RNAseq of hnRNPC and ADAR deficient THP-1
Homo sapiens
132 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 |
| SRR14711269_GSM5352706 | RNA-Seq | 12.5 GB |
| SRR14711270_GSM5352707 | RNA-Seq | 13.9 GB |
| SRR14711271_GSM5352708 | RNA-Seq | 14.4 GB |
| SRR14711272_GSM5352709 | RNA-Seq | 14.0 GB |
| SRR14711273_GSM5352710 | RNA-Seq | 14.2 GB |
| SRR14711274_GSM5352711 | RNA-Seq | 13.0 GB |
| SRR14711275_GSM5352712 | RNA-Seq | 10.2 GB |
| SRR14711276_GSM5352713 | RNA-Seq | 10.5 GB |
| SRR14711277_GSM5352714 | RNA-Seq | 10.7 GB |
| SRR14711278_GSM5352715 | RNA-Seq | 11.2 GB |
| SRR14711279_GSM5352716 | RNA-Seq | 11.2 GB |
| SRR14711280_GSM5352717 | RNA-Seq | 11.5 GB |
| SRR14711281_GSM5352718 | RNA-Seq | 10.2 GB |
| SRR14711282_GSM5352719 | RNA-Seq | 9.5 GB |
| SRR14711283_GSM5352720 | RNA-Seq | 10.3 GB |
| SRR14711284_GSM5352721 | RNA-Seq | 11.1 GB |
| SRR14711285_GSM5352722 | RNA-Seq | 11.7 GB |
| SRR14711286_GSM5352723 | RNA-Seq | 11.4 GB |
| SRR14711287_GSM5352724 | RNA-Seq | 10.4 GB |
| SRR14711288_GSM5352725 | RNA-Seq | 10.7 GB |
| SRR14711289_GSM5352726 | RNA-Seq | 11.1 GB |
| SRR14711290_GSM5352727 | RNA-Seq | 10.0 GB |
| SRR14711291_GSM5352728 | RNA-Seq | 11.2 GB |
| SRR14711292_GSM5352729 | RNA-Seq | 11.5 GB |
| SRR14711293_GSM5352730 | RNA-Seq | 11.2 GB |
| SRR14711294_GSM5352731 | RNA-Seq | 10.5 GB |
| SRR14711295_GSM5352732 | RNA-Seq | 10.5 GB |
| SRR14711296_GSM5352733 | RNA-Seq | 9.3 GB |
| SRR14711297_GSM5352734 | RNA-Seq | 11.1 GB |
| SRR14711298_GSM5352735 | RNA-Seq | 11.9 GB |
| SRR14711299_GSM5352736 | RNA-Seq | 10.7 GB |
| SRR14711300_GSM5352737 | RNA-Seq | 10.5 GB |
| SRR14711301_GSM5352738 | RNA-Seq | 10.1 GB |
| SRR14711302_GSM5352739 | RNA-Seq | 10.3 GB |
| SRR14711303_GSM5352740 | RNA-Seq | 10.6 GB |
| SRR14711304_GSM5352741 | RNA-Seq | 12.3 GB |
| SRR14711305_GSM5352742 | RNA-Seq | 9.6 GB |
| SRR14711306_GSM5352743 | RNA-Seq | 8.7 GB |
| SRR14711307_GSM5352744 | RNA-Seq | 9.4 GB |
| SRR14711308_GSM5352745 | RNA-Seq | 10.7 GB |
| SRR14711309_GSM5352746 | RNA-Seq | 10.1 GB |
| SRR14711310_GSM5352747 | RNA-Seq | 8.5 GB |
| SRR14711311_GSM5352748 | RNA-Seq | 7.9 GB |
| SRR14711312_GSM5352749 | RNA-Seq | 7.8 GB |
| SRR14711313_GSM5352750 | RNA-Seq | 9.6 GB |
| SRR14711314_GSM5352751 | RNA-Seq | 8.3 GB |
| SRR14711315_GSM5352752 | RNA-Seq | 8.6 GB |
| SRR14711316_GSM5352753 | RNA-Seq | 9.4 GB |
| SRR14711317_GSM5352754 | RNA-Seq | 8.8 GB |
| SRR14711318_GSM5352755 | RNA-Seq | 7.9 GB |
| SRR14711319_GSM5352756 | RNA-Seq | 7.8 GB |
| SRR14711320_GSM5352757 | RNA-Seq | 9.1 GB |
| SRR14711321_GSM5352758 | RNA-Seq | 9.2 GB |
| SRR14711322_GSM5352759 | RNA-Seq | 8.3 GB |
| SRR14711323_GSM5352694 | RNA-Seq | 10.2 GB |
| SRR14711324_GSM5352695 | RNA-Seq | 10.9 GB |
| SRR14711325_GSM5352696 | RNA-Seq | 11.1 GB |
| SRR14711326_GSM5352697 | RNA-Seq | 10.4 GB |
| SRR14711327_GSM5352698 | RNA-Seq | 14.3 GB |
| SRR14711328_GSM5352699 | RNA-Seq | 13.8 GB |
| SRR14711329_GSM5352700 | RNA-Seq | 12.3 GB |
| SRR14711330_GSM5352701 | RNA-Seq | 13.3 GB |
| SRR14711331_GSM5352702 | RNA-Seq | 13.9 GB |
| SRR14711332_GSM5352703 | RNA-Seq | 12.4 GB |
| SRR14711333_GSM5352704 | RNA-Seq | 13.0 GB |
| SRR14711334_GSM5352705 | RNA-Seq | 12.2 GB |
Potentially related datasets 2
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.
| Accession | Source | Title |
|---|---|---|
| E-MTAB-1371 | E-MTAB · ArrayExpress | No title in the index |
| GSE176012 | GSE · GEO GEO ↗ | RNAseq of hnRNPC and ADAR deficient THP-1 |
Analysis pipelines 1
| Pipeline | Assay | Steps | Dataset |
|---|---|---|---|
| GSE176012 RNA-seq Data Processing geo_data_processing | RNA-seq | 12 | GSE176012 |
Funding 6 grants
| Grant | Funder |
|---|---|
| R00 HG009530 | NHGRI NIH HHS (United States) |
| U41 HG009889 | NHGRI NIH HHS (United States) |
| K99 HG009530 | NHGRI NIH HHS (United States) |
| U54 HG007005 | NHGRI NIH HHS (United States) |
| U54HG007005 | NHGRI NIH HHS (United States) |
| HG009530 | NHGRI NIH HHS (United States) |