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Annual Review of Immunology

Volume 43, 2025

Genetic Regulation of Cell Death: Insights from Autoinflammatory Diseases

  • Hirotsugu Oda1,2, Alessandro Annibaldi3, Daniel L. Kastner4 and Ivona Aksentijevich4
  • 1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; email: [email protected] 2Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany 3Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany 4National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, Maryland, USA; email: [email protected]
  • Vol. 43:313-342 (Volume publication date April 2025)
  •  
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

Metazoans have evolved innate antimicrobial defenses that promote cellular survival and proliferation. Countering the inevitable molecular mechanisms by which microbes sabotage these pathways, multicellular organisms rely on an alternative, perhaps more ancient, strategy that is the immune equivalent of suicide bombing: Infection triggers cell death programs that summon localized or even systemic inflammation. The study of human genetics has now unveiled a level of complexity that refutes the naive view that cell death is merely a blunt instrument or an evolutionary afterthought. To the contrary, findings from patients with rare diseases teach us that cell death–induced inflammation is a sophisticated, tightly choreographed process. We herein review the emerging body of evidence describing a group of illnesses—inborn errors of cell death, which define many of the molecular building blocks and regulatory elements controlling cell death–induced inflammation in humans—and provide a possible road map to countering this process across the spectrum of rare and common illnesses.

Keyword(s): apoptosis, autoinflammatory diseases, cell death, IECDs, inborn errors of cell death, mutations, necroptosis, NF-κB, TNF, ubiquitylation
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2025-04-25
2025-06-19
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Genetic Regulation of Cell Death: Insights from Autoinflammatory Diseases
Annual Review of Immunology 43, 313 (2025); https://doi.org/10.1146/annurev-immunol-090222-105848
/content/journals/10.1146/annurev-immunol-090222-105848
/content/journals/10.1146/annurev-immunol-090222-105848
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