ISGylation-independent protection of cell growth by USP18 following interferon stimulation.

Clancy, Anne ORCID: 0000-0001-8873-0849, Rusilowicz-Jones, Emma V, Wallace, Iona ORCID: 0000-0003-1673-8651, Swatek, Kirby N, Urbé, Sylvie and Clague, Michael J ORCID: 0000-0003-3355-9479 (2023) ISGylation-independent protection of cell growth by USP18 following interferon stimulation. The Biochemical journal, 480 (19). pp. 1571-1581.

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Official URL: http://dx.doi.org/10.1042/bcj20230301

Abstract

Type 1 interferon stimulation highly up-regulates all elements of a ubiquitin-like conjugation system that leads to ISGylation of target proteins. An ISG15-specific member of the deubiquitylase family, USP18, is up-regulated in a co-ordinated manner. USP18 can also provide a negative feedback by inhibiting JAK-STAT signalling through protein interactions independently of DUB activity. Here, we provide an acute example of this phenomenon, whereby the early expression of USP18, post-interferon treatment of HCT116 colon cancer cells is sufficient to fully suppress the expression of the ISG15 E1 enzyme, UBA7. Stimulation of lung adenocarcinoma A549 cells with interferon reduces their growth rate but they remain viable. In contrast, A549 USP18 knock-out cells show similar growth characteristics under basal conditions, but upon interferon stimulation, a profound inhibition of cell growth is observed. We show that this contingency on USP18 is independent of ISGylation, suggesting non-catalytic functions are required for viability. We also demonstrate that global deISGylation kinetics are very slow compared with deubiquitylation. This is not influenced by USP18 expression, suggesting that enhanced ISGylation in USP18 KO cells reflects increased conjugating activity.

Item Type:	Article
Uncontrolled Keywords:	HCT116 Cells, Humans, Ubiquitin Thiolesterase, Interferon Type I, Ubiquitin
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	21 Dec 2023 16:53
Last Modified:	21 Dec 2023 16:53
DOI:	10.1042/bcj20230301
Open Access URL:	https://doi.org/10.1042/BCJ20230301
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3177599