ISG15’s crucial antiviral role is bolstered by the variety of viral evasion strategies targeting the ISGylation pathway, either by interfering with ISG15 conjugation 1, 13 or by expressing ISG15-specific proteases that lead to reversible 14, 15, 16, 17 or irreversible deconjugation 18. In fact, cells or mice which lack ISG15 are unable to control various viral pathogens including clinically relevant etiologic agents such as Influenza 9, human respiratory syncytial virus 10, and coxsackievirus 11, 12. ![]() ISG15 has potent antiviral effects both in vitro and in vivo 8. ISG15 and its conjugation machinery are strongly upregulated by Type I and III interferon, viral nucleic acids 1, bacterial DNA 6, and lipopolysaccharide (LPS) 7. Similar to ubiquitin, ISG15 conjugates via its C-terminus to lysine residues of substrate proteins in a process called ISGylation, which is mediated by an E1 enzyme, UBE1L, an E2 enzyme, UBCH8, and three known E3 enzymes, HHARI, TRIM25, and HERC5 1, 2, 3, 4, 5. ISG15 is a ubiquitin-like (UBL) protein with antimicrobial activity. Together, our findings provide molecular insights into the ISGylation pathway and reveal RNF213 as a key antimicrobial effector. 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. We report that interferon induces ISGylation and oligomerization of RNF213 on lipid droplets, where it acts as a sensor for ISGylated proteins. RNF213 is a poorly characterized, interferon-induced megaprotein that is frequently mutated in Moyamoya disease, a rare cerebrovascular disorder. 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. ![]() 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. Nature Communications volume 12, Article number: 5772 ( 2021) ![]() Ring finger protein 213 assembles into a sensor for ISGylated proteins with antimicrobial activity
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