Switching Roles

Science Signaling  07 Jul 2009:
Vol. 2, Issue 78, pp. ec226
DOI: 10.1126/scisignal.278ec226

Because of the potent antiviral responses elicited by type I interferons (IFNs) they are used in therapies against a number of diseases. IFN-mediated activation of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway is very well characterized; however, regulation of the expression of IFN-simulated genes (ISGs) is still not completely understood (see commentary by Ozato). Xu et al. compared the IFN-induced gene expression profiles of two human renal cancer cell lines with differing sensitivities to IFN and found that the expression of a subset of ISGs was greater in the more sensitive cell line and that the promoters of those genes contained binding sites for the transcriptional repressor protein promyelocytic leukemia zinc finger (PLZF). PLZF-deficient mice were more susceptible than wild-type (WT) mice to infection by viruses, and IFN-dependent induction of genes important in the antiviral response was impaired in PLZF-deficient mice. In addition, the ability of natural killer (NK) cells to lyse target cells was defective in mice lacking PLZF. Reporter assays showed that PLZF increased the expression of ISGs, and chromatin immunoprecipitation assays demonstrated an interaction between PLZF and the promoter regions of these genes that was enhanced by IFN. In response to IFN, PLZF was phosphorylated and associated with histone deacetylase 1 (HDAC1) and the transcription factor promyelocytic leukemia protein (PML). The authors suggest that phosphorylation and deacetylation of PLZF switches it from being a transcriptional repressor to being an activator. Together, these data suggest that PLZF is an important component of the innate immune response that is required for the expression of IFN-responsive genes.

D. Xu, M. Holko, A. J. Sadler, B. Scott, S. Higashiyama, W. Berkofsky-Fessler, M. J. McConnell, P. P. Pandolfi, J. D. Licht, B. R. G. Williams, Promyelocytic leukemia zinc finger protein regulates interferon-mediated innate immunity. Immunity 30, 802–816 (2009). [PubMed]

K. Ozato, PLZF outreach: A finger in interferon’s pie. Immunity 30, 757–758 (2009). [PubMed]