ADAR and hnRNPC deficiency synergize in activating endogenous dsRNA-induced type I IFN responses
© 2021 Genentech, Inc..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:218 |
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| Enthalten in: |
The Journal of experimental medicine - 218(2021), 9 vom: 06. Sept. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Herzner, Anna-Maria [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.11.2021 Date Revised 24.11.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1084/jem.20201833 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM328419540 |
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| 100 | 1 | |a Herzner, Anna-Maria |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a ADAR and hnRNPC deficiency synergize in activating endogenous dsRNA-induced type I IFN responses |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 24.11.2021 | ||
| 500 | |a Date Revised 24.11.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 Genentech, Inc. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a HNRNPC protein, human |2 NLM | |
| 650 | 7 | |a Heterogeneous-Nuclear Ribonucleoprotein Group C |2 NLM | |
| 650 | 7 | |a IFI27 protein, human |2 NLM | |
| 650 | 7 | |a Interferon Type I |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a RNA, Double-Stranded |2 NLM | |
| 650 | 7 | |a RNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a ADAR protein, human |2 NLM | |
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| 700 | 1 | |a Khan, Zia |e verfasserin |4 aut | |
| 700 | 1 | |a Van Nostrand, Eric L |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Cuellar, Trinna |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ronald |e verfasserin |4 aut | |
| 700 | 1 | |a Pechuan-Jorge, Ximo |e verfasserin |4 aut | |
| 700 | 1 | |a Komuves, Laszlo |e verfasserin |4 aut | |
| 700 | 1 | |a Solon, Margaret |e verfasserin |4 aut | |
| 700 | 1 | |a Modrusan, Zora |e verfasserin |4 aut | |
| 700 | 1 | |a Haley, Benjamin |e verfasserin |4 aut | |
| 700 | 1 | |a Yeo, Gene W |e verfasserin |4 aut | |
| 700 | 1 | |a Behrens, Timothy W |e verfasserin |4 aut | |
| 700 | 1 | |a Albert, Matthew L |e verfasserin |4 aut | |
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