Journal article
The autoantigen TRIM21 assembles proinflammatory immune complexes after lytic cell death
- Abstract:
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Sjögren’s disease (SjD) causes localized and systemic inflammation and autoantibody production against intracellular proteins such as TRIM21/Ro52 (tripartite motif-containing protein 21). TRIM21, an E3 ubiquitin ligase, binds antibody Fc domains on opsonized pathogens that have escaped extracellular immunity and entered the cytosol. TRIM21 then ubiquitinates these pathogens, driving their proteasomal degradation. How TRIM21 becomes an autoantigen remains unclear. We show that TRIM21 is released upon lytic cell death (pyroptosis or necroptosis) but not apoptosis. Although many cytosolic proteins are released by dead cells, liberated TRIM21 is distinct: Its high antibody affinity enables binding to Fc domains of circulating immunoglobulins, forming large immune complexes (ICs). These ICs increase in SjD, where anti-TRIM21 autoantibodies interact with released TRIM21 via Fc and F(ab′)2. TRIM21 ICs are taken up by macrophages, which drive proinflammatory responses, antigen presentation, and metabolic changes in high interferon environments. Thus, TRIM21 may perpetuate inflammation and autoantigen presentation, resulting in high immunogenicity.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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Access Document
- Files:
-
-
(Preview, Accepted manuscript, pdf, 11.0MB, Terms of use)
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- Publisher copy:
- 10.1126/sciimmunol.ads9680
Authors
- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MR/W001217/1
- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 224343/Z/21/Z
- Grant:
- KENN 20 21 12
- KENN 21 22 02
- KENN 19 20 01
- Grant:
- R39207CN121
- Funder identifier:
- https://ror.org/05ccjmp23
- Publisher:
- American Association for the Advancement of Science
- Journal:
- Science Immunology More from this journal
- Volume:
- 11
- Issue:
- 118
- Article number:
- eads9680
- Publication date:
- 2026-04-17
- Acceptance date:
- 2026-03-26
- DOI:
- EISSN:
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2470-9468
- Pmid:
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41996473
- Language:
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English
- Pubs id:
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2395382
- Local pid:
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pubs:2395382
- Deposit date:
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2026-06-09
- ARK identifier:
Terms of use
- Copyright holder:
- Jones Evans 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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