Identification of USP18 as an important regulator of the susceptibility to IFN-alpha and drug-induced apoptosis.
Gene products that modify the apoptotic susceptibility of cancer cells may offer novel drug response markers or therapeutic targets. In this study, we probed the contribution of 53 different isopeptidases to apoptosis triggered by bortezomib and etoposide. USP18, a type I IFN-induced protein that deconjugates the ubiquitin-like modifier ISG15 from target proteins, was found to limit apoptotic susceptibility to IFN-alpha or bortezomib. Ablating USP18 in cells treated with IFN-alpha increased tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) production; upregulated expression of transcription factors IFN-regulatory factor (IRF)-1, IRF-7, and IRF-9; and promoted the extrinsic pathway of apoptosis. The proapoptotic effects of ablating USP18 were abrogated by FLIP overexpression or TRAIL silencing. However, in bortezomib-treated cells, weak spontaneous signaling from type I IFNs was implicated in the proapoptotic effect of USP18 ablation. Ectopic USP18 repressed apoptotic signaling by IFN-alpha, TRAIL, or bortezomib. Similar effects were produced by a catalytically inactive USP18 mutant, indicating that the antiapoptotic function of USP18 is independent of its catalytic activity. These findings suggest that USP18 may significantly limit operation of the extrinsic apoptotic pathway triggered by type I IFN and drugs.
Potu
Harish
H
Dipartimento di Scienze e Tecnologie Biomediche, Universita' di Udine, 33100 Udine, Italy.
Sgorbissa
Andrea
A
Brancolini
Claudio
C
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D019759:Carbon-Nitrogen Lyases / Q000037:antagonists & inhibitors / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D010450:Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology; D020868:Gene Silencing; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D043222:Ubiquitin Thiolesterase
D001897:Boronic Acids; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011480:Protease Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000069286:Bortezomib; D005047:Etoposide; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase; D019759:Carbon-Nitrogen Lyases; C034300:isopeptidase