M1-linked ubiquitination by LUBAC regulates AMPK signalling and the response to energetic stress
Year: 2026
Type: article
Abstract: Methionine-1 (M1)-linked ubiquitin chains, assembled by the linear ubiquitin chain assembly complex (LUBAC) and disassembled by the deubiquitinase OTULIN, are critical regulators of inflammation and immune homoeostasis. Genetic loss or mutation of the LUBAC subunits HOIP and HOIL-1 or of OTULIN causes autoinflammatory syndromes accompanied by metabolic defects, including amylopectinosis, lipodystrophy, and fatty liver disease. Yet, it remains unclear how LUBAC and OTULIN control metabolic signalling. Here, we demonstrate that LUBAC and OTULIN dynamically regulate the energy-sensing kinase AMPK, a central sensor and switch for cellular and organismal energy balance. LUBAC's activity through the catalytic subunit HOIP is required for full AMPK activation in response to energetic stress, whereas OTULIN antagonises this response. LUBAC and OTULIN form a complex with AMPK, and LUBAC can directly ubiquitinate AMPKα and β subunits in cells and in vitro, establishing AMPK as a bona fide M1-linked ubiquitin substrate. Loss of LUBAC blunts AMPK activation, reduces bioenergetic adaptability, impairs autophagy, and sensitises cells to starvation-induced death, while Drosophila lacking Lubel - the fly orthologue of LUBAC - exhibit defective AMPK activation and reduced survival during starvation. Our findings identify M1-linked ubiquitination as a previously unrecognised regulatory layer controlling AMPK activation, metabolic adaptability, and the cellular response to energetic stress.
Source: Cell Death and Differentiation
Authors: Camilla Reiter Elbæk, Sophie Gradinaru, Anna M. Dahlström, Alexander Frueh, Akhee S. Jahan, Joyceline Cuenco, Anna L. Aalto, John Rizk, Simon A. Hawley, Sarah N. J. Franks, Michael Stumpe, Srinivasa Prasad Kolapalli, Chris Kedong Wang, Cara J. Ellison, Ximena Hildebrandt, Klara Nielsen, Dominik Priesmann, Julian Koch, Mathilde Deichmann, Josef Gullmets, Lien Verboom, Geert van Loo, Nieves Peltzer, Lisa B. Frankel, Paul R. Elliott, Mads Gyrd-Hansen, Jörn Dengjel, Brent J. Ryan, D. Grahame Hardie, Annika Meinander, Kei Sakamoto, Rune Busk Damgaard
Institutions: Barcelona Institute of Science and Technology, Centre for Genomic Regulation, Technical University of Denmark, Åbo Akademi University, University of Copenhagen, Novo Nordisk Foundation Center for Basic Metabolic Research, LEO Foundation, University of Dundee, University of Oxford, University of Fribourg, Danish Cancer Society, University of Stuttgart, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Ghent University, VIB-UGent Center for Inflammation Research
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,790
Funders: National Science Foundation, Kræftens Bekæmpelse, Uddannelses- og Forskningsministeriet, University of Dundee, Wellcome Trust, UK Research and Innovation, Deutsche Forschungsgemeinschaft, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Academy of Finland, Eidgenössische Technische Hochschule Zürich, Novo Nordisk, Danmarks Frie Forskningsfond, Danmarks Tekniske Universitet, Åbo Akademi, Novo Nordisk Fonden, Biocenter Finland, Medical Research Council
Awards: G1129915825, Multi-level mapping of mitochondrial quality control pathways in Parkinson's dopaminergic neurons, G1669649860, Role of AMPK in Nutrient Sensing and in Cancer, G1868306760, InFLAMES: Innovation Ecosystem based on the Immune System, G3971737914, G4230908485, G4504918650, Role of AMPK in Nutrient Sensing and in Cancer, G4536697403, Making herbicide markets: Interactions between production restructuring, agriculture and environment in Latin America and Asia, SFB 1403: Zelltod in Immunität, Entzündungen und Erkrankungen, G7119488142, G76067623, G8221995800, G8263706436, G8351935874, G8623766528
OpenAlex ID: W7128806348