Universität zu Köln

Nagata, Masahiro, Carvalho Schäfer, Yasmin ORCID: 0009-0007-5978-8858, Wachsmuth, Laurens ORCID: 0000-0003-1701-9384 and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2024). A shorter splicing isoform antagonizes ZBP1 to modulate cell death and inflammatory responses. The EMBO Journal, 43 (21). pp. 5037-5056. Springer Nature. ISSN 1460-2075

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Abstract

[Artikel-Nr.: 12] 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.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Nagata, Masahiro UNSPECIFIED UNSPECIFIED UNSPECIFIED Carvalho Schäfer, Yasmin UNSPECIFIED https://orcid.org/0009-0007-5978-8858 UNSPECIFIED Wachsmuth, Laurens UNSPECIFIED https://orcid.org/0000-0003-1701-9384 UNSPECIFIED Pasparakis, Manolis UNSPECIFIED https://orcid.org/0000-0002-9870-0966 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-814933
Identification Number:	10.1038/s44318-024-00238-7
Journal or Publication Title:	The EMBO Journal
Volume:	43
Number:	21
Page Range:	pp. 5037-5056
Number of Pages:	20
Date:	19 September 2024
Publisher:	Springer Nature
ISSN:	1460-2075
Language:	English
Faculty:	Central Institutions / Interdisciplinary Research Centers Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	Life sciences Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language ZBP1 ; Necroptosis ; Cell Death ; Inflammation English
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81493