Ring Finger Protein 213 Assembles into a Sensor for ISGylated Proteins with Antimicrobial Activity

Thery, F.; Martina, L.; Asselman, C.; Repo, H.; Zhang, Y.; Sedeyn, K.; Moschonas, G. D.; Bredow, C.; Teo, Q. W.; Zhang, J.; Vessely, M.; Leandro, K.; Eggermont, D.; De Sutter, D.; Boucher, K.; Hochepied, T.; Festjens, N.; Callewaert, N.; Saelens, X.; Dermaut, B.; Knobeloch, K.-P.; Beling, A.; Sanyal, S.; Radoshevich, L.; Eyckerman, S.; Impens, F.

doi:10.1101/2021.06.03.446796

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bioRxiv · 10.1101/2021.06.03.446796

Ring Finger Protein 213 Assembles into a Sensor for ISGylated Proteins with Antimicrobial Activity

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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 used a viral-like particle trapping technology to identify ISG15-binding proteins and discovered 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 found that interferon induces ISGylation and oligomerization of RNF213 on lipid droplets, where it acts as a sensor for ISGylated proteins. We showed that RNF213 has broad antimicrobial activity in vitro and in vivo, counteracting infection with Listeria monocytogenes, herpes simplex virus 1 (HSV-1), human respiratory syncytial virus (RSV) and coxsackievirus B3 (CVB3), and we observed a striking co-localization of RNF213 with intracellular bacteria. Together, our findings provide novel molecular insights into the ISGylation pathway and reveal RNF213 as a key antimicrobial effector.

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Thery, F., Martina, L., Asselman, C., Repo, H., Zhang, Y., Sedeyn, K., Moschonas, G. D., Bredow, C., Teo, Q. W., Zhang, J., Vessely, M., Leandro, K., Eggermont, D., De Sutter, D., Boucher, K., Hochepied, T., Festjens, N., Callewaert, N., Saelens, X., Dermaut, B., Knobeloch, K.-P., Beling, A., Sanyal, S., Radoshevich, L., Eyckerman, S., Impens, F.. 2021-06-03. Ring Finger Protein 213 Assembles into a Sensor for ISGylated Proteins with Antimicrobial Activity. https://doi.org/10.1101/2021.06.03.446796

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