Journal article
Upstream ORFs control TNFR1 abundance and tissue tolerance to TNF
- Abstract:
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Tumor necrosis factor (TNF) orchestrates immune responses but can also drive inflammation-associated tissue damage. However, the mechanisms governing tissue tolerance to TNF remain poorly understood. Here, we reveal that TNF receptor 1 (TNFR1) abundance is regulated by two upstream open reading frames (uORFs) in the 5′ untranslated region of TNFRSF1A and demonstrate that this is a key determinant of TNF tolerance. uORF2 dominantly limits TNFR1 translation, and its disruption increases TNFR1 levels, leading to excessive TNF-induced gene activation and cell death in cell culture. By contrast, uORF1 dynamically regulates TNFR1 levels in response to inflammatory and stress signals. In mice, uORF2 protects against TNF-driven systemic inflammatory response syndrome and liver pathology. We additionally report that the translation of other immune receptor messenger RNAs, including TLR4, IFNAR1, and IFNGR2, is also controlled by uORFs. Thus, regulation of TNFR1 levels and possibly of other immune receptors emerges as a mechanism safeguarding against excessive immune responses and tissue damage.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
-
-
(Preview, Accepted manuscript, pdf, 23.3MB, Terms of use)
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- Publisher copy:
- 10.1126/sciimmunol.aeb6484
Authors
- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 102894/Z/13/Z
- Funder identifier:
- https://ror.org/054225q67
- Grant:
- CRUK-OC-DPhil17-BM
- Funder identifier:
- https://ror.org/04txyc737
- Grant:
- NNF200C0059392
- Funder identifier:
- https://ror.org/00yjd3n13
- Grant:
- P300P3_155374
- Publisher:
- American Association for the Advancement of Science
- Journal:
- Science Immunology More from this journal
- Volume:
- 11
- Issue:
- 118
- Article number:
- eaeb6484
- Publication date:
- 2026-04-03
- Acceptance date:
- 2026-03-11
- DOI:
- EISSN:
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2470-9468
- Pmid:
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41931597
- Language:
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English
- Keywords:
- Pubs id:
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2403281
- Local pid:
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pubs:2403281
- Deposit date:
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2026-04-17
- ARK identifier:
Terms of use
- Copyright holder:
- Ma et al.
- Copyright date:
- 2026
- Rights statement:
- Copyright © 2026 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
- Notes:
- The author accepted manuscript (AAM) of this paper has been made available under the University of Oxford's Open Access Publications Policy, and a CC BY public copyright licence has been applied.
- Licence:
- CC Attribution (CC BY)
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