---
DOAJ_listed: '1'
OA_place: publisher
OA_type: gold
PlanS_conform: '1'
_id: '22772'
abstract:
- lang: eng
text: The cytoplasmic antiviral sensor MDA5 is activated by double-stranded RNAs.
Endogenous double-stranded RNAs are modified by the A-to-I RNA-editing ADAR family
to prevent activation of MDA5. In vivo, cytoplasmic ADAR1p150 is critically required
to suppress MDA5 activation, yet the editing signature of all ADAR isoforms is
strongly overlapping in mice. Further, it is not clear how A-to-I modifications
in dsRNA prevent MDA5 activation. Here we show that 3′ UTRs harboring inverted
repeats activate MDA5 in vitro and in cells. In vitro editing by either ADAR isoform
leads to editing at overlapping hotspot regions and prevents MDA5 activation in
vitro and in cells. Remarkably, only inosines introduced by RNA editing are capable
of suppressing MDA5 activation, while replacing guanosines with inosines during
in vitro transcription has no impact on MDA5 activation. A comparison of inosines
introduced by ADAR1p150 in vitro, in cells, and in vivo suggests that a small
number of A-to-I conversions may be critically required to suppress MDA5 activation.
As those critical editing events are predominantly altering A:U basepairs into
I:U wobble basepairs, we suggest that the helical distortion introduced by those
wobble pairs may prevent MDA5 polymerization and thus downstream activation of
the type I interferon response.
acknowledgement: This work was supported by Austrian Science Fund project F80-07 to
M.F.J., F80-03 to C.B., and ZK57-B28 to C.V.; National Health and Medical Research
Council Australia (NHMRC; GNT2018098 to C.R.W.). The work was supported in part
by the Victorian State Government Operational Infrastructure Support Scheme to St
Vincent’s Institute and Hudson Institute of Medical Research. R.V. and A.L. were
supported by Doc Fund/DOC32 of the Austrian Science Fund. Funding to pay the Open
Access publication charges for this article was provided by Austrian Science Fund.
For open access purposes, the author has applied a CC BY public copyright license
to any author accepted manuscript version arising from this submission.
article_number: gkag845
article_processing_charge: Yes
article_type: original
author:
- first_name: Rajagopal
full_name: Varada, Rajagopal
last_name: Varada
- first_name: Alina F.
full_name: Leuchtenberger, Alina F.
last_name: Leuchtenberger
- first_name: Cornelia
full_name: Vesely, Cornelia
last_name: Vesely
- first_name: Beata M
full_name: Kaczmarek, Beata M
id: 36FA4AFA-F248-11E8-B48F-1D18A9856A87
last_name: Kaczmarek
- first_name: Hamid
full_name: Mansouri Khosravi, Hamid
last_name: Mansouri Khosravi
- first_name: Therese C.
full_name: Mandl, Therese C.
last_name: Mandl
- first_name: Katarina
full_name: Milanovic, Katarina
last_name: Milanovic
- first_name: Kasra
full_name: Honarmand Tamizkar, Kasra
last_name: Honarmand Tamizkar
- first_name: Vinod
full_name: Rajendra, Vinod
last_name: Rajendra
- first_name: Hannes
full_name: Senoner, Hannes
last_name: Senoner
- first_name: Linda
full_name: Steinbichl, Linda
last_name: Steinbichl
- first_name: Marija
full_name: Borojevic, Marija
last_name: Borojevic
- first_name: Andy
full_name: Sombke, Andy
last_name: Sombke
- first_name: Katy
full_name: Schmidt, Katy
last_name: Schmidt
- first_name: Margret
full_name: Eckhard, Margret
last_name: Eckhard
- first_name: Ivo L.
full_name: Hofacker, Ivo L.
last_name: Hofacker
- first_name: Carl
full_name: Walkley, Carl
last_name: Walkley
- first_name: Jacki E.
full_name: Heraud-Farlow, Jacki E.
last_name: Heraud-Farlow
- first_name: Ernesto
full_name: Picardi, Ernesto
last_name: Picardi
- first_name: Carrie A
full_name: Bernecky, Carrie A
id: 2CB9DFE2-F248-11E8-B48F-1D18A9856A87
last_name: Bernecky
orcid: 0000-0003-0893-7036
- first_name: Michael F.
full_name: Jantsch, Michael F.
last_name: Jantsch
citation:
ama: Varada R, Leuchtenberger AF, Vesely C, et al. Distinguishing self from non-self
RNA by editing-specific inosine patterns. Nucleic Acids Research. 2026;54(16).
doi:10.1093/nar/gkag845
apa: Varada, R., Leuchtenberger, A. F., Vesely, C., Kaczmarek, B. M., Mansouri Khosravi,
H., Mandl, T. C., … Jantsch, M. F. (2026). Distinguishing self from non-self RNA
by editing-specific inosine patterns. Nucleic Acids Research. Oxford University
Press. https://doi.org/10.1093/nar/gkag845
chicago: Varada, Rajagopal, Alina F. Leuchtenberger, Cornelia Vesely, Beata M Kaczmarek,
Hamid Mansouri Khosravi, Therese C. Mandl, Katarina Milanovic, et al. “Distinguishing
Self from Non-Self RNA by Editing-Specific Inosine Patterns.” Nucleic Acids
Research. Oxford University Press, 2026. https://doi.org/10.1093/nar/gkag845.
ieee: R. Varada et al., “Distinguishing self from non-self RNA by editing-specific
inosine patterns,” Nucleic Acids Research, vol. 54, no. 16. Oxford University
Press, 2026.
ista: Varada R, Leuchtenberger AF, Vesely C, Kaczmarek BM, Mansouri Khosravi H,
Mandl TC, Milanovic K, Honarmand Tamizkar K, Rajendra V, Senoner H, Steinbichl
L, Borojevic M, Sombke A, Schmidt K, Eckhard M, Hofacker IL, Walkley C, Heraud-Farlow
JE, Picardi E, Bernecky C, Jantsch MF. 2026. Distinguishing self from non-self
RNA by editing-specific inosine patterns. Nucleic Acids Research. 54(16), gkag845.
mla: Varada, Rajagopal, et al. “Distinguishing Self from Non-Self RNA by Editing-Specific
Inosine Patterns.” Nucleic Acids Research, vol. 54, no. 16, gkag845, Oxford
University Press, 2026, doi:10.1093/nar/gkag845.
short: R. Varada, A.F. Leuchtenberger, C. Vesely, B.M. Kaczmarek, H. Mansouri Khosravi,
T.C. Mandl, K. Milanovic, K. Honarmand Tamizkar, V. Rajendra, H. Senoner, L. Steinbichl,
M. Borojevic, A. Sombke, K. Schmidt, M. Eckhard, I.L. Hofacker, C. Walkley, J.E.
Heraud-Farlow, E. Picardi, C. Bernecky, M.F. Jantsch, Nucleic Acids Research 54
(2026).
das_tickbox: '1'
dataavailabilitystatement: "Sequencing data has been deposited at GEO and is available
under accession number GSE293616.\r\nEditing analysis of protected dsRNA is available
in GitHub, https://github.com/BioinfoUNIBA/Mouse-dsRNA-mda5, and Zenodo, https://doi.org/10.5281/zenodo.17876716."
date_created: 2026-08-30T22:01:44Z
date_published: 2026-09-09T00:00:00Z
date_updated: 2026-09-09T11:31:04Z
day: '09'
ddc:
- '570'
department:
- _id: CaBe
- _id: GradSch
doi: 10.1093/nar/gkag845
external_id:
pmid:
- '42635125'
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date_created: 2026-09-09T11:29:49Z
date_updated: 2026-09-09T11:29:49Z
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fulldoi: https://doi.org/10.1093/nar/gkag845
has_accepted_license: '1'
intvolume: ' 54'
issue: '16'
language:
- iso: eng
month: '09'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 8dc144d4-16d5-11f0-9cad-9d9e86aea1f7
grant_number: F8003
name: 'RNAdeco: decorating RNA for a purpose/ P03- Roles of A-to-I editing in dsRNA
recognition'
publication: Nucleic Acids Research
publication_identifier:
eissn:
- 1362-4962
publication_status: published
publisher: Oxford University Press
quality_controlled: '1'
researchdata_availability: yes
scopus_import: '1'
status: public
supplementarymaterial: yes
title: Distinguishing self from non-self RNA by editing-specific inosine patterns
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 54
year: '2026'
...