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ISG15 - Interferon Stimulated Gene 15

ISG15 is an interferon-induced ubiquitin-like protein with anti-viral and anti-bacterial properties.  ISG15 has three known modes of action: 


1) It can act as a cytokine

2) It can non-covalently sequester viral or host proteins which are required for infection

3) It can covalently target viral and host proteins to combat infection.


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Though ISG15 was the first identified ubiquitin-like protein, very little is known about its mechanism of action.  We focus on understanding how ISGylation alters the fate and function of target proteins. ISG15 has been challenging to study because it is not conserved in yeast, there is not yet an established in vitro system and modification following overexpression of ISG15, the E1, E2 and E3 in cell lines is predominantly co-translational and somewhat non specific presumably to target viral proteins. We recently took advantage of existing mouse models engineered by Klaus-Peter Knobeloch to establish a method to identify sites of modification on target proteins using label-free, quantitative mass spectrometry. 


We devised a genetic strategy to differentiate between ISG15 and Ubiquitin sites on target proteins following Listeria monocytogenes infection.  We identified 934 sites, which made up nearly 20% of di-glycine sites from the liver following infection. We are currently using this technology to determine the ISGylome in a variety of tissues and both bacterial and viral infections . 

Zhang Y, Thery F, Wu NC, Luhmann EK, Dussurget O, Foecke M, Bredow C, Jiménez-Fernández D, Leandro K, Beling A, Knobeloch KP, Impens F, Cossart P, Radoshevich L. The in vivo ISGylome links ISG15 to metabolic pathways and autophagy upon Listeria monocytogenes infection. Nat Commun. 2019 Nov 26;10(1):5383.

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