Pyrin inflammasome-driven erosive arthritis caused by unprenylated RHO GTPase signaling
- Author
- Muralikrishna Akula (UGent) , Elisabeth Gilis (UGent) , Pieter Hertens (UGent) , Lieselotte Vande Walle (UGent) , Mozes Sze (UGent) , Julie Coudenys (UGent) , Yunus Incik (UGent) , Omar Khan, Martin O. Bergo, Dirk Elewaut (UGent) , Andy Wullaert (UGent) , Mohamed Lamkanfi (UGent) and Geert van Loo (UGent)
- Organization
- Project
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- Targeting the mevalonate pathway to treat inflammatory diseases
- Novel mechanisms of inflammation and cell death regulation in autoinflammatory and infectious diseases
- Investigating itaconic acid as a critical immunometabolite in Influenza and RSV infections
- Host-microbe interaction in intestinal homeostasis: unravelling the mechanisms involved in the onset of multiple inflammation-related diseases
- The impact of cell death on the cancer stem cell niche in non-melanoma skin cancer
- Evaluating the function and the therapeutic potential of IFN-λ in intestinal carcinogenesis
- Going viral – how does murine norovirus alter intestinal immunity in the host and across generations?
- Charcot Stichting - Fund 2022: Investigating itaconic acid as a critical immunometabolite in multiple sclerosis
- Single cell analysis of inflammasome-mediated IL-1ß secretion in primary human monocytes
- Regulation of the Nlrp1a inflammasome in cutaneous and systemic autoinflammation
- Targeting NLRP3-mediated inflammation with novel chemotypes
- Investigating the effects of regulatory phosphorylation and linear ubiquitination on Pyrin-mediated auto-inflammatory disorders.
- Cell Death Regulation and Role in Infection and Inflammatory Diseases
- OTULIN in neuroinflammation an Alzheimer pathology
- Dissecting cellular interactions underlying auto-inflammation in Familial Mediterranean Fever
- Abstract
- Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, serves as the substrate for protein geranylgeranylation, a process catalyzed by geranylgeranyl transferase I (GGTase-I). Myeloid-specific deletion of Pggt1b, the gene coding for GGTase-I, leads to spontaneous and severe erosive arthritis in mice; however, the underlying mechanisms remained unclear. In this study, we demonstrate that arthritis in mice with myeloid-specific Pggt1b deficiency is driven by unprenylated GTP-bound small RHO family GTPases, which in turn trigger Pyrin (Mefv) inflammasome activation, GSDMD-dependent macrophage pyroptosis, and IL-1 beta secretion. We show that although Pggt1b deficiency leads to hyperactivation of RAC1, impaired prenylation alters its proper membrane localization and interaction with effectors, rendering it effectively inactive in vivo. Consequently, unprenylated RHO family signaling promotes Pyrin inflammasome assembly through recruitment to the RAC1 effector IQGAP1. Together, these findings identify a novel inflammatory axis in which non-prenylated RHO GTPase activity promotes spontaneous Pyrin inflammasome activation, pyroptosis, and IL-1 beta release in macrophages, contributing to inflammatory arthritis in mice.
- Keywords
- SMALL-MOLECULE INHIBITOR, PROTEIN, CELL, PRENYLATION, MECHANISMS, ACTIVATION, CASPASE-1, DEFICIENT, EHT-1864, RECEPTOR, RHO Family GTPases, Prenylation, Pyrin Inflammasome, Pyroptosis, Arthritis
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01KA0RZAB8VJG4KQNWNX08TBRJ
- MLA
- Akula, Muralikrishna, et al. “Pyrin Inflammasome-Driven Erosive Arthritis Caused by Unprenylated RHO GTPase Signaling.” EMBO MOLECULAR MEDICINE, vol. 17, no. 10, 2025, pp. 2691–712, doi:10.1038/s44321-025-00298-0.
- APA
- Akula, M., Gilis, E., Hertens, P., Vande Walle, L., Sze, M., Coudenys, J., … van Loo, G. (2025). Pyrin inflammasome-driven erosive arthritis caused by unprenylated RHO GTPase signaling. EMBO MOLECULAR MEDICINE, 17(10), 2691–2712. https://doi.org/10.1038/s44321-025-00298-0
- Chicago author-date
- Akula, Muralikrishna, Elisabeth Gilis, Pieter Hertens, Lieselotte Vande Walle, Mozes Sze, Julie Coudenys, Yunus Incik, et al. 2025. “Pyrin Inflammasome-Driven Erosive Arthritis Caused by Unprenylated RHO GTPase Signaling.” EMBO MOLECULAR MEDICINE 17 (10): 2691–2712. https://doi.org/10.1038/s44321-025-00298-0.
- Chicago author-date (all authors)
- Akula, Muralikrishna, Elisabeth Gilis, Pieter Hertens, Lieselotte Vande Walle, Mozes Sze, Julie Coudenys, Yunus Incik, Omar Khan, Martin O. Bergo, Dirk Elewaut, Andy Wullaert, Mohamed Lamkanfi, and Geert van Loo. 2025. “Pyrin Inflammasome-Driven Erosive Arthritis Caused by Unprenylated RHO GTPase Signaling.” EMBO MOLECULAR MEDICINE 17 (10): 2691–2712. doi:10.1038/s44321-025-00298-0.
- Vancouver
- 1.Akula M, Gilis E, Hertens P, Vande Walle L, Sze M, Coudenys J, et al. Pyrin inflammasome-driven erosive arthritis caused by unprenylated RHO GTPase signaling. EMBO MOLECULAR MEDICINE. 2025;17(10):2691–712.
- IEEE
- [1]M. Akula et al., “Pyrin inflammasome-driven erosive arthritis caused by unprenylated RHO GTPase signaling,” EMBO MOLECULAR MEDICINE, vol. 17, no. 10, pp. 2691–2712, 2025.
@article{01KA0RZAB8VJG4KQNWNX08TBRJ,
abstract = {{Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, serves as the substrate for protein geranylgeranylation, a process catalyzed by geranylgeranyl transferase I (GGTase-I). Myeloid-specific deletion of Pggt1b, the gene coding for GGTase-I, leads to spontaneous and severe erosive arthritis in mice; however, the underlying mechanisms remained unclear. In this study, we demonstrate that arthritis in mice with myeloid-specific Pggt1b deficiency is driven by unprenylated GTP-bound small RHO family GTPases, which in turn trigger Pyrin (Mefv) inflammasome activation, GSDMD-dependent macrophage pyroptosis, and IL-1 beta secretion. We show that although Pggt1b deficiency leads to hyperactivation of RAC1, impaired prenylation alters its proper membrane localization and interaction with effectors, rendering it effectively inactive in vivo. Consequently, unprenylated RHO family signaling promotes Pyrin inflammasome assembly through recruitment to the RAC1 effector IQGAP1. Together, these findings identify a novel inflammatory axis in which non-prenylated RHO GTPase activity promotes spontaneous Pyrin inflammasome activation, pyroptosis, and IL-1 beta release in macrophages, contributing to inflammatory arthritis in mice.}},
author = {{Akula, Muralikrishna and Gilis, Elisabeth and Hertens, Pieter and Vande Walle, Lieselotte and Sze, Mozes and Coudenys, Julie and Incik, Yunus and Khan, Omar and Bergo, Martin O. and Elewaut, Dirk and Wullaert, Andy and Lamkanfi, Mohamed and van Loo, Geert}},
issn = {{1757-4676}},
journal = {{EMBO MOLECULAR MEDICINE}},
keywords = {{SMALL-MOLECULE INHIBITOR,PROTEIN,CELL,PRENYLATION,MECHANISMS,ACTIVATION,CASPASE-1,DEFICIENT,EHT-1864,RECEPTOR,RHO Family GTPases,Prenylation,Pyrin Inflammasome,Pyroptosis,Arthritis}},
language = {{eng}},
number = {{10}},
pages = {{2691--2712}},
title = {{Pyrin inflammasome-driven erosive arthritis caused by unprenylated RHO GTPase signaling}},
url = {{http://doi.org/10.1038/s44321-025-00298-0}},
volume = {{17}},
year = {{2025}},
}
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