2. Academic Validation
  3. LUBAC enables tumor-promoting LTβ receptor signaling by activating canonical NF-κB

LUBAC enables tumor-promoting LTβ receptor signaling by activating canonical NF-κB

  • Cell Death Differ. 2024 Oct;31(10):1267-1284. doi: 10.1038/s41418-024-01355-w.
Yu-Guang Chen 1 2,  Eva Rieser 1 3 4,  Amandeep Bhamra 5,  Silvia Surinova 5,  Peter Kreuzaler 3 4,  Meng-Hsing Ho 6,  Wen-Chiuan Tsai 7,  Nieves Peltzer # 4 8 9,  Diego de Miguel # 1 3 4 10,  Henning Walczak # 11 12 13
Affiliations

Affiliations

  • 1 Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
  • 2 Division of Hematology/Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
  • 3 Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
  • 4 CECAD Research Centre, University of Cologne, Cologne, Germany.
  • 5 Proteomics Research Translational Technology Platform, UCL Ciancer Institute and Cancer Research UK UCL Centre, University College London (UCL), London, UK.
  • 6 Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
  • 7 Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
  • 8 Department of Translational Genomics and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Medical Faculty, Cologne, Germany.
  • 9 Department of Genome Editing, University of Stuttgart, Stuttgart, Germany.
  • 10 Aragon Health Research Institute (IIS Aragon), Biomedical Research Centre of Aragon (CIBA), Zaragoza, Spain.
  • 11 Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK. h.walczak@uni-koeln.de.
  • 12 Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany. h.walczak@uni-koeln.de.
  • 13 CECAD Research Centre, University of Cologne, Cologne, Germany. h.walczak@uni-koeln.de.
  • # Contributed equally.
PMID: 39215104 DOI: 10.1038/s41418-024-01355-w
Abstract

Lymphotoxin β Receptor (LTβR), a member of the TNF Receptor Superfamily (TNFR-SF), is essential for development and maturation of lymphoid organs. In addition, LTβR activation promotes carcinogenesis by inducing a proinflammatory secretome. Yet, we currently lack a detailed understanding of LTβR signaling. In this study we discovered the linear ubiquitin chain assembly complex (LUBAC) as a previously unrecognized and functionally crucial component of the native LTβR signaling complex (LTβR-SC). Mechanistically, LUBAC-generated linear ubiquitin chains enable recruitment of NEMO, OPTN and A20 to the LTβR-SC, where they act coordinately to regulate the balance between canonical and non-canonical NF-κB pathways. Thus, different from death receptor signaling, where LUBAC prevents inflammation through inhibition of cell death, in LTβR signaling LUBAC is required for inflammatory signaling by enabling canonical and interfering with non-canonical NF-κB activation. This results in a LUBAC-dependent LTβR-driven inflammatory, protumorigenic secretome. Intriguingly, in liver Cancer patients with high LTβR expression, high expression of LUBAC correlates with poor prognosis, providing clinical relevance for LUBAC-mediated inflammatory LTβR signaling.

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