M1-linked ubiquitination by LUBAC regulates AMPK signalling and the response to energetic stress

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.

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Journal
Cell Death and Differentiation
Published
2026-02-13
DOI
https://doi.org/10.1038/s41418-026-01675-z
Primary Topic
Ubiquitin and proteasome pathways
Type
article
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M1-linked ubiquitination by LUBAC regulates AMPK signalling and the response to energetic stress

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Ubiquitin and proteasome pathways
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M1-linked ubiquitination by LUBAC regulates AMPK signalling and the response to energetic stress

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article en

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.

Cell Death and Differentiation
University of Stuttgart (DE), University of Copenhagen (DK), Åbo Akademi University (FI), University of Fribourg (CH), University of Dundee (GB), University of Cologne (DE), Novo Nordisk Foundation (DK), Ghent University (BE), University of Oxford (GB), Parkinson's UK (GB), LEO Foundation (DK), Centre for Genomic Regulation (ES), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), VIB-UGent Center for Inflammation Research (BE), Science Oxford (GB), Danish Cancer Society (DK), Technical University of Denmark (DK)
National Science Foundation, 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 Tekniske Universitet, Novo Nordisk Fonden, Biocenter Finland, Medical Research Council
Openalex Percentile: Top 57%
Ubiquitin and proteasome pathways
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