2. Academic Validation
  3. RIPK1 is required for ZBP1-driven necroptosis in human cells

RIPK1 is required for ZBP1-driven necroptosis in human cells

  • PLoS Biol. 2025 Feb 21;23(2):e3002845. doi: 10.1371/journal.pbio.3002845.
Oluwamuyiwa T Amusan 1,  Shuqi Wang 1,  Chaoran Yin 2,  Heather S Koehler 3,  Yixun Li 1,  Tencho Tenev 4,  Rebecca Wilson 4,  Benjamin Bellenie 5,  Ting Zhang 2,  Jian Wang 1 6,  Chang Liu 7,  Kim Seong 1,  Seyedeh L Poorbaghi 1,  Joseph Yates 1,  Yuchen Shen 1,  Jason W Upton 8,  Pascal Meier 4,  Siddharth Balachandran 2,  Hongyan Guo 1
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America.
  • 2 Blood Cell Development and Function, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
  • 3 School of Molecular Biosciences, Washington State University, Pullman, Washington State, United States of America.
  • 4 The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, United Kingdom.
  • 5 Centre for Cancer Drug Discovery at the Institute of Cancer Research, London, United Kingdom.
  • 6 Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America.
  • 7 Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
  • 8 Department of Biological Sciences, Auburn University, Auburn, Alabama, United States of America.
PMID: 39982916 DOI: 10.1371/journal.pbio.3002845
Abstract

Necroptosis initiated by the host sensor Z-NA binding protein 1 (ZBP1) is essential for host defense against a growing number of viruses, including herpes simplex virus 1 (HSV-1). Studies with HSV-1 and Other necroptogenic stimuli in murine settings have suggested that ZBP1 triggers Necroptosis by directly complexing with the kinase RIPK3. Whether this is also the case in human cells, or whether additional co-factors are needed for ZBP1-mediated Necroptosis, is unclear. Here, we show that ZBP1-induced Necroptosis in human cells requires RIPK1. We have found that RIPK1 is essential for forming a stable and functional ZBP1-RIPK3 complex in human cells, but is dispensable for the formation of the equivalent murine complex. The receptor-interacting protein (RIP) homology interaction motif (RHIM) in RIPK3 is responsible for this difference between the 2 species, because replacing the RHIM in human RIPK3 with the RHIM from murine RIPK3 is sufficient to overcome the requirement for RIPK1 in human cells. These observations describe a critical mechanistic difference between mice and humans in how ZBP1 engages in Necroptosis, with important implications for treating human diseases.

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