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

Fabien Thery, Lia Martina, Caroline Asselman, Yifeng Zhang, Madeleine Vessely, Heidi Repo, Koen Sedeyn, George D. Moschonas, Clara Bredow, Qi Wen Teo, Jingshu Zhang, Kevin Leandro, Denzel Eggermont, Delphine Sutter, Katie Boucher, Tino Hochepied, Nele Festjens, Nico Callewaert, Xavier Saelens, Bart Dermaut, Klaus-Peter Knobeloch, Antje Beling, Sumana Sanyal, Lilliana Radoshevich (), Sven Eyckerman () and Francis Impens ()
Additional contact information
Fabien Thery: VIB-UGent Center for Medical Biotechnology, VIB
Lia Martina: VIB-UGent Center for Medical Biotechnology, VIB
Caroline Asselman: VIB-UGent Center for Medical Biotechnology, VIB
Yifeng Zhang: University of Iowa Carver College of Medicine
Madeleine Vessely: University of Iowa Carver College of Medicine
Heidi Repo: VIB-UGent Center for Medical Biotechnology, VIB
Koen Sedeyn: VIB-UGent Center for Medical Biotechnology, VIB
George D. Moschonas: VIB-UGent Center for Medical Biotechnology, VIB
Clara Bredow: Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Biochemistry
Qi Wen Teo: University of Hong Kong
Jingshu Zhang: University of Hong Kong
Kevin Leandro: VIB-UGent Center for Medical Biotechnology, VIB
Denzel Eggermont: VIB-UGent Center for Medical Biotechnology, VIB
Delphine Sutter: VIB-UGent Center for Medical Biotechnology, VIB
Katie Boucher: VIB-UGent Center for Medical Biotechnology, VIB
Tino Hochepied: VIB Center for Inflammation Research, VIB
Nele Festjens: VIB-UGent Center for Medical Biotechnology, VIB
Nico Callewaert: VIB-UGent Center for Medical Biotechnology, VIB
Xavier Saelens: VIB-UGent Center for Medical Biotechnology, VIB
Bart Dermaut: Ghent University
Klaus-Peter Knobeloch: University of Freiburg
Antje Beling: Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Biochemistry
Sumana Sanyal: University of Hong Kong
Lilliana Radoshevich: University of Iowa Carver College of Medicine
Sven Eyckerman: VIB-UGent Center for Medical Biotechnology, VIB
Francis Impens: VIB-UGent Center for Medical Biotechnology, VIB

Nature Communications, 2021, vol. 12, issue 1, 1-21

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26061-w

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