Ring finger protein 213 assembles into a sensor for ISGylated proteins with antimicrobial activity PMID: 34599178

GLP-1 and Obesity Research

2026-08-18

Ring finger protein 213 assembles into a sensor for ISGylated proteins with antimicrobial activity

Nat Commun. 2021 Oct 1;12(1):5772. doi: 10.1038/s41467-021-26061-w.

Fabien Thery ^# ¹ ² , Lia Martina ^# ¹ ² , Caroline Asselman ^# ¹ ² , Yifeng Zhang ³ , Madeleine Vessely ³ , Heidi Repo ¹ ² , Koen Sedeyn ¹ ⁴ , George D Moschonas ¹ ⁴ , Clara Bredow ⁵ , Qi Wen Teo ⁶ , Jingshu Zhang ⁶ , Kevin Leandro ¹ ² , Denzel Eggermont ¹ ² , Delphine De Sutter ¹ ² , Katie Boucher ¹ ² ⁷ , Tino Hochepied ⁸ ⁹ , Nele Festjens ¹ ⁴ , Nico Callewaert ¹ ⁴ , Xavier Saelens ¹ ⁴ , Bart Dermaut ² ¹⁰ , Klaus-Peter Knobeloch ¹¹ , Antje Beling ⁵ ¹² , Sumana Sanyal ⁶ ¹³ , Lilliana Radoshevich ¹⁴ , Sven Eyckerman ¹⁵ ¹⁶ , Francis Impens ¹⁷ ¹⁸ ¹⁹

Affiliations

1. VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium.
2. Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
3. Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
4. Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium.
5. Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Biochemistry, Berlin, Germany.
6. HKU-Pasteur Research Pole, School of Public Health, University of Hong Kong, Pok Fu Lam, Hong Kong.
7. VIB Proteomics Core, VIB, Ghent, Belgium.
8. VIB Center for Inflammation Research, VIB, Ghent, Belgium.
9. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
10. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
11. Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany.
12. Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner side Berlin, Berlin, Germany.
13. Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK.
14. Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, IA, USA. [email protected].
15. VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium. [email protected].
16. Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. [email protected].
17. VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium. [email protected].
18. Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. [email protected].
19. VIB Proteomics Core, VIB, Ghent, Belgium. [email protected].
# Contributed equally.

Abstract

ISG15 is an interferon-stimulated, ubiquitin-like protein that can conjugate to substrate proteins (ISGylation) to counteract microbial Infection, but the underlying mechanisms remain elusive. Here, we use a virus-like particle trapping technology to identify ISG15-binding proteins and discover Ring Finger Protein 213 (RNF213) as an ISG15 interactor and cellular sensor of ISGylated proteins. RNF213 is a poorly characterized, interferon-induced megaprotein that is frequently mutated in Moyamoya disease, a rare cerebrovascular disorder. We report that interferon induces ISGylation and oligomerization of RNF213 on lipid droplets, where it acts as a sensor for ISGylated proteins. We show that RNF213 has broad antimicrobial activity in vitro and in vivo, counteracting Infection with Listeria monocytogenes, herpes simplex virus 1, human respiratory syncytial virus and coxsackievirus B3, and we observe a striking co-localization of RNF213 with intracellular bacteria. Together, our findings provide molecular insights into the ISGylation pathway and reveal RNF213 as a key antimicrobial effector.