LUBAC enables tumor-promoting LTβ receptor signaling by activating canonical NF-κB PMID: 39215104

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
12. Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany. [email protected].
13. CECAD Research Centre, University of Cologne, Cologne, Germany. [email protected].
# Contributed equally.

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.