title: The interferon stimulated gene 54 promotes apoptosis.
abstract: The ability of interferons (IFNs) to inhibit viral replication and cellular proliferation is well established, but the specific contribution of each IFN-stimulated gene (ISG) to these biological responses remains to be completely understood. In this report we demonstrate that ISG54, also known as IFN-induced protein with tetratricopeptide repeats 2 (IFIT2), is a mediator of apoptosis. Expression of ISG54, independent of IFN stimulation, elicits apoptotic cell death. Cell death and apoptosis were quantified by propidium iodide uptake and annexin-V staining, respectively. The activation of caspase-3, a key mediator of the execution phase of apoptosis, was clearly apparent in cells expressing ISG54. The anti-apoptotic B cell lymphoma-xl (Bcl-xl) protein inhibited the apoptotic effects of ISG54 as did the anti-apoptotic adenoviral E1B-19K protein. In addition, ISG54 was not able to promote cell death in the absence of pro-apoptotic Bcl family members, Bax and Bak. Analyses of binding partners of ISG54 revealed association with two homologous proteins, ISG56/IFIT1 and ISG60/IFIT3. In addition, ISG60 binding negatively regulates the apoptotic effects of ISG54. The results reveal a previously unidentified role of ISG54 in the induction of apoptosis via a mitochondrial pathway and shed new light on the mechanism by which IFN elicits anti-viral and anti-cancer effects.
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University Stony Brook, New York 11794, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Stawowczyk
authors.forename: Sarah
authors.initials: S
authors.lastname: Van Scoy
authors.forename: K Prasanna
authors.initials: KP
authors.lastname: Kumar
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Reich
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D051379:Mice; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C484290:IFIT1 protein, human; C484289:IFIT2 protein, human; C116468:IFIT3 protein, human; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014157:Transcription Factors