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J. Biol. Chem., Vol. 281, Issue 36, 26188-26195, September 8, 2006

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Toll-like Receptor-dependent and -independent Viperin Gene Expression and Counter-regulation by PRDI-binding Factor-1/BLIMP1^*

Martina Severa, Eliana M. Coccia, and Katherine A. Fitzgerald¹

From the Division of Infectious Disease and Immunology, Department of Medicine, The University of Massachusetts Medical School, Worcester, Massachusetts 01605 and the Department of Infectious, Parasitic, and Immuno-Mediated Diseases, Istituto Superiore di Sanita, Viale Regina Elena 299, 00161 Rome, Italy

Here we identify Viperin as a highly inducible gene in response to lipopolysaccharide (LPS), double-stranded RNA (poly(I-C)) or Sendai virus (SV). The only known function of Viperin relates to its ability to inhibit human Cytomegalovirus replication. Very little data are available on the regulation of this gene. In silico analysis of the promoter identified two interferon (IFN)-stimulated response elements (ISRE), which in other genes bind IRF3 or the IFN-stimulated gene factor-3 (ISGF3) complex. LPS and poly(I-C) induce very high levels of Viperin in wild type cells but not in cells deficient in TRIF, TBK1, IRF3, or the type I IFN/R. SV-induced Viperin gene expression was mediated independently of Toll-like receptor (TLR) signaling by retinoic acid-inducible gene (RIG-I) and the downstream adapter, mitochondrial anti-viral signaling (MAVS). Virus-induced Viperin expression was not attenuated in macrophages deficient in either TBK1 or IKK alone. Moreover, IRF3-deficient, but not IFN/R deficient, macrophages still induced Viperin in response to SV. Promoter reporter studies combined with DNA immunoprecipitation assays identified the ISGF3 complex as the key regulator of Viperin gene expression. Moreover, positive regulatory domain I-binding factor 1 (PRDI-BF1, also called BLIMP1) binds the ISRE sites and competes with ISGF3 binding in a virus inducible manner to inhibit Viperin transcription. Collectively, these studies identify Viperin as a tightly regulated ISGF3 target gene, which is counter-regulated by PRDI-BF1.

Received for publication, May 11, 2006 , and in revised form, July 12, 2006.

^* This work was supported by National Institutes of Health Grant AI067497-01 (to K. A. F.) and Grant 5AD/F4 from the Italian Ministry of Health (to E. M. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 508-856-6518; Fax: 508-856-5463; E-mail: kate.fitzgerald{at}umassmed.edu.

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