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

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

doi:10.1038/s41418-026-01675-z

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

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 (Lead / Corresponding author)

Cell Signalling and Immunology

Research output: Contribution to journal › Article › peer-review

5 Downloads (Pure)

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.

Original language	English
Journal	Cell Death and Differentiation
Early online date	13 Feb 2026
DOIs	https://doi.org/10.1038/s41418-026-01675-z
Publication status	Published - 13 Feb 2026

ASJC Scopus subject areas

Molecular Biology
Cell Biology

Access to Document

10.1038/s41418-026-01675-zLicence: CC BY

Final published version
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Final published version, 6.56 MBLicence: CC BY

Cite this

Elbæk, C. R., Gradinaru, S., Dahlström, A. M., Frueh, A., Jahan, A. S., Cuenco, J., Aalto, A. L., Rizk, J., Hawley, S. A., Franks, S. N. J., Stumpe, M., Kolapalli, S. P., Wang, C. K., Ellison, C. J., Hildebrandt, X., Nielsen, K., Priesmann, D., Koch, J., Deichmann, M., ... Damgaard, R. B. (2026). M1-linked ubiquitination by LUBAC regulates AMPK signalling and the response to energetic stress. Cell Death and Differentiation. https://doi.org/10.1038/s41418-026-01675-z

@article{4b657d165bc444d9bf298396d2c27cd4,

title = "M1-linked ubiquitination by LUBAC regulates AMPK signalling and the response to energetic stress",

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{\textquoteright}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.",

author = "Elb{\ae}k, \{Camilla Reiter\} and Sophie Gradinaru and Dahlstr{\"o}m, \{Anna M.\} and Alexander Frueh and Jahan, \{Akhee S.\} and Joyceline Cuenco and Aalto, \{Anna L.\} and John Rizk and Hawley, \{Simon A.\} and Franks, \{Sarah N.J.\} and Michael Stumpe and Kolapalli, \{Srinivasa Prasad\} and Wang, \{Chris Kedong\} and Ellison, \{Cara J.\} and Ximena Hildebrandt and Klara Nielsen and Dominik Priesmann and Julian Koch and Mathilde Deichmann and Josef Gullmets and Lien Verboom and \{van Loo\}, Geert and Nieves Peltzer and Frankel, \{Lisa B.\} and Elliott, \{Paul R.\} and Mads Gyrd-Hansen and J{\"o}rn Dengjel and Ryan, \{Brent J.\} and Hardie, \{D. Grahame\} and Annika Meinander and Kei Sakamoto and Damgaard, \{Rune Busk\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2026.",

year = "2026",

month = feb,

day = "13",

doi = "10.1038/s41418-026-01675-z",

language = "English",

journal = "Cell Death and Differentiation",

issn = "1350-9047",

publisher = "Springer Nature",

}

Elbæk, CR, Gradinaru, S, Dahlström, AM, Frueh, A, Jahan, AS, Cuenco, J, Aalto, AL, Rizk, J, Hawley, SA, Franks, SNJ, Stumpe, M, Kolapalli, SP, Wang, CK, Ellison, CJ, Hildebrandt, X, Nielsen, K, Priesmann, D, Koch, J, Deichmann, M, Gullmets, J, Verboom, L, van Loo, G, Peltzer, N, Frankel, LB, Elliott, PR, Gyrd-Hansen, M, Dengjel, J, Ryan, BJ, Hardie, DG, Meinander, A, Sakamoto, K & Damgaard, RB 2026, 'M1-linked ubiquitination by LUBAC regulates AMPK signalling and the response to energetic stress', Cell Death and Differentiation. https://doi.org/10.1038/s41418-026-01675-z

TY - JOUR

T1 - M1-linked ubiquitination by LUBAC regulates AMPK signalling and the response to energetic stress

AU - Elbæk, Camilla Reiter

AU - Gradinaru, Sophie

AU - Dahlström, Anna M.

AU - Frueh, Alexander

AU - Jahan, Akhee S.

AU - Cuenco, Joyceline

AU - Aalto, Anna L.

AU - Rizk, John

AU - Hawley, Simon A.

AU - Franks, Sarah N.J.

AU - Stumpe, Michael

AU - Kolapalli, Srinivasa Prasad

AU - Wang, Chris Kedong

AU - Ellison, Cara J.

AU - Hildebrandt, Ximena

AU - Nielsen, Klara

AU - Priesmann, Dominik

AU - Koch, Julian

AU - Deichmann, Mathilde

AU - Gullmets, Josef

AU - Verboom, Lien

AU - van Loo, Geert

AU - Peltzer, Nieves

AU - Frankel, Lisa B.

AU - Elliott, Paul R.

AU - Gyrd-Hansen, Mads

AU - Dengjel, Jörn

AU - Ryan, Brent J.

AU - Hardie, D. Grahame

AU - Meinander, Annika

AU - Sakamoto, Kei

AU - Damgaard, Rune Busk

PY - 2026/2/13

Y1 - 2026/2/13

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105030209562

U2 - 10.1038/s41418-026-01675-z

DO - 10.1038/s41418-026-01675-z

M3 - Article

C2 - 41688728

AN - SCOPUS:105030209562

SN - 1350-9047

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Role of AMPK in Nutrient Sensing and in Cancer (Investigator Award Renewal)

Cite this

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

Role of AMPK in Nutrient Sensing and in Cancer (Investigator Award Renewal)

Cite this