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A ZBP1 isoform blocks ZBP1-mediated cell death.
- Source :
-
Cell reports [Cell Rep] 2024 May 28; Vol. 43 (5), pp. 114221. Date of Electronic Publication: 2024 May 14. - Publication Year :
- 2024
-
Abstract
- ZBP1 is an interferon (IFN)-induced nucleic acid (NA) sensor that senses unusual Z-form NA (Z-NA) to promote cell death and inflammation. However, the mechanisms that dampen ZBP1 activation to fine-tune inflammatory responses are unclear. Here, we characterize a short isoform of ZBP1 (referred to as ZBP1-S) as an intrinsic suppressor of the inflammatory signaling mediated by full-length ZBP1. Mechanistically, ZBP1-S depresses ZBP1-mediated cell death by competitive binding with Z-NA for Zα domains of ZBP1. Cells from mice (Ripk1 <superscript>D325A/D325A</superscript> ) with cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome are alive but sensitive to IFN-induced and ZBP1-dependent cell death. Intriguingly, Ripk1 <superscript>D325A/D325A</superscript> cells die spontaneously when ZBP1-S is deleted, indicating that cell death driven by ZBP1 is under the control of ZBP1-S. Thus, our findings reveal that alternative splicing of Zbp1 represents autogenic inhibition for regulating ZBP1 signaling and indicate that uncoupling of Z-NA with ZBP1 could be an effective strategy against autoinflammations.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Mice
Humans
Receptor-Interacting Protein Serine-Threonine Kinases metabolism
Signal Transduction
Mice, Inbred C57BL
Alternative Splicing genetics
HEK293 Cells
Inflammation metabolism
Inflammation pathology
RNA-Binding Proteins metabolism
RNA-Binding Proteins genetics
Cell Death
Protein Isoforms metabolism
Protein Isoforms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 43
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 38748877
- Full Text :
- https://doi.org/10.1016/j.celrep.2024.114221