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A shorter splicing isoform antagonizes ZBP1 to modulate cell death and inflammatory responses

Masahiro Nagata1,2, Yasmin Carvalho Schäfer1,2, Laurens Wachsmuth1,2

  • 1Institute for Genetics, University of Cologne, D-50674, Cologne, Germany.

The EMBO Journal
|September 19, 2024
PubMed

Insights

A newly discovered short ZBP1 isoform (ZBP1-S) inhibits full-length ZBP1-L, acting as a crucial regulator of Z-DNA-mediated cell death and inflammation.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Death Research

Background:

  • Z-DNA-binding protein 1 (ZBP1) is an interferon-inducible sensor protein.
  • ZBP1 regulates cell death and inflammation by binding Z-DNA/Z-RNA and interacting with RIPK1/RIPK3.
  • The precise regulation of ZBP1 activity in vivo is not fully understood.

Purpose of the Study:

  • To investigate the existence and function of alternatively spliced ZBP1 isoforms.
  • To determine the role of a newly identified ZBP1 isoform in regulating ZBP1-mediated cell death and inflammation.

Main Methods:

  • Analysis of ZBP1 splicing variants in mice.
  • Cellular and in vivo studies using knockout and knockdown models.
  • Assessment of cell death, necroptosis, and inflammatory responses.

Main Results:

  • Identification of an alternatively spliced ZBP1 isoform, ZBP1-S, lacking RIP homotypic interaction motifs (RHIMs).
  • ZBP1-S acts as an endogenous inhibitor of full-length ZBP1-L by competing for Z-nucleic acid binding.
  • Mice and cells lacking ZBP1-S exhibit heightened ZBP1-L-induced cell death and inflammation, particularly skin inflammation.

Conclusions:

  • ZBP1-S is a critical endogenous inhibitor that fine-tunes ZBP1-L activity.
  • This regulatory mechanism is essential for preventing excessive ZBP1-mediated cell death and inflammation.
  • ZBP1-S plays a significant physiological role in immune homeostasis and inflammatory control.
Keywords:
Cell DeathInflammationNecroptosisZBP1

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