ADAR and hnRNPC deficiency synergize in activating endogenous dsRNA-induced type I IFN responses
| Autor: | Matthew L. Albert, Zia Khan, Margaret Solon, Trinna L. Cuellar, Timothy W. Behrens, Anna-Maria Herzner, Benjamin Haley, László G. Kömüves, Eric L. Van Nostrand, Gene W. Yeo, Ronald Chen, Zora Modrusan, Sara Chan, Ximo Pechuan-Jorge |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
HNRNPC Interferon-Induced Helicase IFIH1 Adenosine Deaminase THP-1 Cells Immunology Innate Immunity and Inflammation Alu element Autoimmunity Biology Article 03 medical and health sciences 0302 clinical medicine Cytosol Alu Elements Immunology and Allergy Humans RNA Double-Stranded Heterogeneous-Nuclear Ribonucleoprotein Group C Intron RNA Membrane Proteins RNA-Binding Proteins MDA5 Introns Cell biology RNA silencing 030104 developmental biology 030220 oncology & carcinogenesis RNA splicing ADAR Interferon Type I MCF-7 Cells RNA Editing CRISPR-Cas Systems |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 |
| Popis: | hnRNPC prevents release of inverted-repeat Alu double-stranded RNA into the cytosol by masking cryptic splice sites. Herzner et al. found that deficiency in hnRNPC led to dysregulation of splicing and increased abundance of intronic double-stranded RNA, which together with ADAR deficiency resulted in a synergistic increase in spontaneous MDA5-dependent IFN responses. 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. Graphical Abstract |
| Databáze: | OpenAIRE |
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