USP16 is an ISG15 cross-reactive deubiquitinase that targets pro-ISG15 and ISGylated proteins involved in metabolism

Interferon-induced ubiquitin (Ub)-like modifier ISG15 covalently modifies host and viral proteins to restrict viral infections. Its function is counteracted by the canonical deISGylase USP18 or Ub-specific protease 18. Notwithstanding indications for the existence of other ISG15 cross-reactive prote...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2023-12, Vol.120 (50), p.e2315163120-e2315163120
Hauptverfasser: Gan, Jin, Pinto-Fernández, Adán, Flierman, Dennis, Akkermans, Jimmy J L L, O'Brien, Darragh P, Greenwood, Helene, Scott, Hannah Claire, Fritz, Günter, Knobeloch, Klaus-Peter, Neefjes, Jacques, van Dam, Hans, Ovaa, Huib, Ploegh, Hidde L, Kessler, Benedikt M, Geurink, Paul P, Sapmaz, Aysegul
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Sprache:eng
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Zusammenfassung:Interferon-induced ubiquitin (Ub)-like modifier ISG15 covalently modifies host and viral proteins to restrict viral infections. Its function is counteracted by the canonical deISGylase USP18 or Ub-specific protease 18. Notwithstanding indications for the existence of other ISG15 cross-reactive proteases, these remain to be identified. Here, we identify deubiquitinase USP16 as an ISG15 cross-reactive protease by means of ISG15 activity-based profiling. Recombinant USP16 cleaved pro-ISG15 and ISG15 isopeptide-linked model substrates in vitro, as well as ISGylated substrates from cell lysates. Moreover, interferon-induced stimulation of ISGylation was increased by depletion of USP16. The USP16-dependent ISG15 interactome indicated that the deISGylating function of USP16 may regulate metabolic pathways. Targeted enzymes include malate dehydrogenase, cytoplasmic superoxide dismutase 1, fructose-bisphosphate aldolase A, and cytoplasmic glutamic-oxaloacetic transaminase 1. USP16 may thus contribute to the regulation of a subset of metabolism-related proteins during type-I interferon responses.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2315163120