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

Journal article

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.

Authors: Gan, J; Pinto-Fernández, A; Flierman, D; Akkermans, JJLL; O'Brien, DP

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: National Academy of Sciences
• Journal: Proceedings of the National Academy of Sciences
• Volume: 120
• Issue: 50
• Article number: e2315163120
• Publication date: 2023-12-06
• Acceptance date: 2023-11-02
• DOI: 10.1073/pnas.2315163120
• EISSN: 1091-6490
• ISSN: 0027-8424
• Language: English
• Keywords: metabolism; activity-based probe; ISGylation; ISG15; FFR; USP16