A shorter splicing isoform antagonizes ZBP1 to modulate cell death and inflammatory responses.
Cell Death
Inflammation
Necroptosis
ZBP1
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
19 Sep 2024
19 Sep 2024
Historique:
received:
22
03
2024
accepted:
20
08
2024
revised:
15
08
2024
medline:
20
9
2024
pubmed:
20
9
2024
entrez:
19
9
2024
Statut:
aheadofprint
Résumé
Z-DNA-binding protein 1 (ZBP1) is an interferon-inducible sensor of Z-DNA and Z-RNA, which has emerged as a critical regulator of cell death and inflammation. ZBP1 binds Z-DNA and Z-RNA via its Zα domains, and signals by engaging RIPK3 and RIPK1 via its RIP homotypic interaction motifs (RHIMs). Here, we show that mice express an alternatively-spliced shorter ZBP1 isoform (ZBP1-S), which harbours the Zα domains but lacks the RHIMs, and acts as an endogenous inhibitor of the full-length protein (ZBP1-L). Mice and cells expressing only ZBP1-S are resistant to ZBP1-mediated cell death and inflammation. In contrast, cells lacking ZBP1-S show increased ZBP1-L-induced death compared to cells expressing both isoforms. Moreover, loss of the short isoform accelerates and exacerbates skin inflammation induced by ZBP1-mediated necroptosis of RIPK1-deficient keratinocytes, revealing an important physiological role of ZBP1-S. Mechanistically, ZBP1-S suppresses ZBP1-L-mediated cell death by binding to Z-nucleic acids via its Zα domains. Therefore, ZBP1-S acts as an endogenous inhibitor that competes with full-length ZBP1-L for binding Z-nucleic acid ligands to fine-tune ZBP1-mediated cell death and inflammation.
Identifiants
pubmed: 39300211
doi: 10.1038/s44318-024-00238-7
pii: 10.1038/s44318-024-00238-7
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : EC | European Research Council (ERC)
ID : 787826
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : 414786233
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : 390661388
Informations de copyright
© 2024. The Author(s).
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