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

Autor: Chen YG; Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.; Division of Hematology/Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan., Rieser E; Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.; Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.; CECAD Research Centre, University of Cologne, Cologne, Germany., Bhamra A; Proteomics Research Translational Technology Platform, UCL Ciancer Institute and Cancer Research UK UCL Centre, University College London (UCL), London, UK., Surinova S; Proteomics Research Translational Technology Platform, UCL Ciancer Institute and Cancer Research UK UCL Centre, University College London (UCL), London, UK., Kreuzaler P; Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.; CECAD Research Centre, University of Cologne, Cologne, Germany., Ho MH; Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan., Tsai WC; Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan., Peltzer N; CECAD Research Centre, University of Cologne, Cologne, Germany.; Department of Translational Genomics and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Medical Faculty, Cologne, Germany.; Department of Genome Editing, University of Stuttgart, Stuttgart, Germany., de Miguel D; Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.; Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.; CECAD Research Centre, University of Cologne, Cologne, Germany.; Aragon Health Research Institute (IIS Aragon), Biomedical Research Centre of Aragon (CIBA), Zaragoza, Spain., Walczak H; Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK. h.walczak@uni-koeln.de.; Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany. h.walczak@uni-koeln.de.; CECAD Research Centre, University of Cologne, Cologne, Germany. h.walczak@uni-koeln.de.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2024 Oct; Vol. 31 (10), pp. 1267-1284. Date of Electronic Publication: 2024 Aug 30.
DOI: 10.1038/s41418-024-01355-w
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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