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Recent Publication

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

Noted Research:

In a trans-Atlantic collaboration, researchers from the labs of Francis Impens (VIB-UGent, Center for Medical Biotechnology) and of Lilliana Radoshevich (Carver College of Medicine, University of Iowa), have shed light on a novel cell intrinsic host defense pathway against intracellular pathogens. ISG15 is a host protein whose activity targets viral and bacterial infection. In this manuscript, Thery and colleagues used a new technique developed at VIB to trap and identify interactors of ISG15 in order to understand its function. Using this method called “virotrap,” they uncovered an interaction between ISG15 and RNF213. RNF213 is a giant protein whose mutation results in Moyamoya disease, which is a rare disorder that causes patients to suffer from stroke at a young age. RNF213 is known to stabilize lipid droplets in the cell but in this manuscript, the authors discovered that it could also serve as a binding platform for ISGylated proteins. Lipid droplets have antibacterial properties and, in this study, RNF213 was shown to dock on and tag the surface of the intracellular bacterium, Listeria monocytogenes with ubiquitin, thus targeting the bacteria for destruction through the cellular recycling pathway of autophagy.  Accordingly, deletion of RNF213 strongly sensitized animals to Listeria monocytogenes infection. This manuscript linking RNF213 to intracellular clearance of viruses and bacteria may help researchers understand and unlock the mysterious etiology of Moyamoya disease.  

 

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.

Authors:
  • Fabien Thery, Lia Martina, Caroline Asselman, Yifeng Zhang, Madeleine Vessely, Heidi Repo, Koen Sedeyn, George D. Moschonas, Clara Bredow, Qi Wen Teo, Jingshu Zhang, K...Lilliana Radoshevich, Sven Eyckerman, Francis Impens