Evidence map›Paper›PMID 41648199›Full record

ArticlebioRxiv : the preprint server for biology2026

Inosine misincorporation into mRNA triggers the integrated stress response and activates an innate immune gene expression signature.

Jacob H Schroader, Naa N Adade, Emmanuel E Adade, Mark A Bratslavsky, Hannah K Shorrock, Bradley R Smith, Ting Zhou, Steven Lotz, Taylor Bertucci, Sally Temple and 6 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors.

Jacob H SchroaderThe RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USA.
Naa N AdadeThe RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USA.
Emmanuel E AdadeThe RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USA.
Mark A BratslavskyThe RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USA.
Hannah K ShorrockThe RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USA.
Bradley R SmithDepartment of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642, USA.
Ting ZhouThe SKI Stem Cell Research Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Steven LotzNeural Stem Cell Institute, Albany, NY 12208 USA.
Taylor BertucciNeural Stem Cell Institute, Albany, NY 12208 USA.
Sally TempleNeural Stem Cell Institute, Albany, NY 12208 USA.
Alex M ValmThe RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USA.
Cara T PagerThe RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USA.
J Andrew BerglundThe RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USA.
Mark T HandleyThe RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USA.
Gabriele FuchsThe RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USA.
Kaalak ReddyThe RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USA.ORCID 0000-0002-1916-0261

Funding

RNA Science and Technology in Health and DiseaseT32GM132066 · NIGMS · STATE UNIVERSITY OF NEW YORK AT ALBANY · PI Thomas J Begley · 2019 to 2026
$1.8M
Oral microbial community structure and assembly: from molecule to microbiomeR01DE030927 · NIDCR · STATE UNIVERSITY OF NEW YORK AT ALBANY · PI VALM, ALEX M · 2021 to 2025
$1.8M
Zeiss LSM 980 Confocal Microscope SystemS10OD028600 · OD · STATE UNIVERSITY OF NEW YORK AT ALBANY · PI VALM, ALEX M · 2022 to 2022
$477k
Functional consequences of ITPase deficiency and the impact of inosine misincorporation into the transcriptomeR21HD119656 · NICHD · STATE UNIVERSITY OF NEW YORK AT ALBANY · PI FUCHS, GABRIELE, REDDY, KAALAK · 2025 to 2025
$423k
NICHD NIH HHS R21 HD119656NIDCR NIH HHS R01 DE030927NIGMS NIH HHS T32 GM132066NIH HHS S10 OD028600
6 · The paper itself

Abstract

The inosine triphosphate pyrophosphatase (ITPase) enzyme restricts levels of the non-canonical nucleotides (deoxy)inosine triphosphate (dITP/ITP) and prevents their aberrant misincorporation into nucleic acids. ITPase deficiency is associated with dilated cardiomyopathy and epileptic encephalopathy in humans and is usually fatal in infancy. It leads to pronounced inosine misincorporation into RNA but the cellular consequences of this misincorporation are not well understood and the pathogenic basis of ITPase deficiency remains unknown. Here we show that cellular transfection of mRNA with inosine misincorporation activates the integrated stress response (ISR) with an innate immune gene expression signature. This stress response triggers stress granule formation and is modulated by the double stranded RNA sensor protein Kinase R (PKR). Inosine nucleoside treatment of ITPase-deficient cells leads to endogenous inosine misincorporation into mRNA and activation of the ISR. Further, differentiation of human ITPase-deficient induced pluripotent stem cells into neurons results in a low-level stress response. Thus, our study establishes inosine misincorporation into mRNA as an unappreciated form of cellular stress. This is normally prevented by the ITPase enzyme, with implications for the pathogenesis of ITPase deficiency.

Identifiers

PMID41648199
PMCPMC12871305

What OpenQuestion holds

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LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.