IRF-5 Is a Mediator of the Death Receptor-induced Apoptotic Signaling Pathway

• Published in: The Journal of biological chemistry Vol. 284; no. 5; pp. 2767 - 2777
• Main Authors: Hu, Guodong, Barnes, Betsy J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.01.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Apoptosis - physiology; Base Sequence; Cell Line; DNA Primers; Flow Cytometry; Humans; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - physiology; Receptors, Death Domain - physiology; Signal Transduction - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M804744200

The efficient and regulated response to cellular stress is coordinated by a genetic regulatory network in which a given transcription factor controls the expression of diverse target genes depending on the cell type and/or nature of the stimuli. The tumor suppressor p53 is thought to preferentially regulate the balance between cell survival and death. The interferon regulatory factor 5 (IRF-5), known to be involved in the innate immune response to pathogens, is also a critical regulator of DNA damage-induced apoptosis. Here, we provide direct evidence that IRF-5 promotes apoptosis upon signaling through tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors (DR). We report that IRF-5 sensitizes tumor cells to TRAIL-induced apoptosis and cell death that is further enhanced by type I interferons. Cells deficient of IRF-5 gave a significantly diminished response to these agents. IRF-5 is involved in DR signaling upstream of caspase 8, in part because of an IRF-5-dependent increase in caspase 8 activation. We provide evidence that TRAIL induces a signaling cascade that leads to the phosphorylation and nuclear localization of IRF-5, resulting in transactivation of key DR signaling components. The results presented here identify IRF-5 as a new mediator of DR signaling and provides molecular insight into the mechanism of TRAIL-induced IRF-5 signaling.