SinoXivLUBAC PUB domain interactions restrict Met1-linked ubiquitination to prevent embryonic lethality and immune pathology
Abstract
Met1-linked ubiquitin (Met1-Ub) assembled by LUBAC crucially regulates immune receptor signalling. However, the regulation of LUBAC’s function remains widely debated. Here, we reveal that the interaction between LUBAC and PUB-interacting motif (PIM)-containing proteins, including deubiquitinases OTULIN and SPATA2-CYLD, safeguards the fidelity of Met1-Ub deposition to prevent embryonic lethality and immune pathology. Mutation of the PUB domain in the LUBAC subunit HOIP ablated PIM-interactions and led to excessive Met1-Ub on signalling components after immune receptor stimulation, yet impaired productive signalling and sensitised to TNF-induced cell death. In vivo, ablation of HOIP PIM-interactions caused embryonic lethality at midgestation and led to acute cytokine storm, immune dysregulation, and weight loss when induced in adult mice. Moreover, heterozygous ablation of HOIP PUB PIM-interactions, which did not cause spontaneous pathology, rendered mice remarkably sensitive to TNF-challenge. Thus, the PUB domain of HOIP is a critical protein-interaction interface regulating LUBAC’s function in receptor signalling and immune homeostasis.
Keywords
Citation Information
@article{madsgyrdhansen2026,
title={LUBAC PUB domain interactions restrict Met1-linked ubiquitination to prevent embryonic lethality and immune pathology},
author={Mads Gyrd-Hansen and John Rizk and Frederik Timmermann and Wenxin Lyu and Kit Lee and Majken Kjær and Miriam Beichler and Berthe Fiil and Malin Jessen and Giulia Franciosa and Jesper Olsen and Max Sauerland and Rune Damgaard and Dominik Priesmann},
journal={Nature Portfolio},
year={2026},
doi={https://doi.org/10.21203/rs.3.rs-5519483/v1}
}
