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Journal of Virology, February 2008, p. 1474-1483, Vol. 82, No. 3
0022-538X/08/$08.00+0     doi:10.1128/JVI.01650-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Negative Feedback Regulation of RIG-I-Mediated Antiviral Signaling by Interferon-Induced ISG15 Conjugation{triangledown}

Min-Jung Kim,1 Sun-Young Hwang,1 Tadaatsu Imaizumi,2 and Joo-Yeon Yoo1*

Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 790-784, Republic of Korea,1 Department of Vascular Biology, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan2

Received 28 July 2007/ Accepted 15 November 2007

RIG-I senses intracellular virus-specific nucleic acid structures and initiates an antiviral response that induces interferon (IFN) production, which, in turn, activates the transcription of RIG-I to increase RIG-I protein levels. Upon intracellular poly(I:C) stimulation, however, the levels of RIG-I protein did not correlate with the expression patterns of RIG-I transcripts. When the ISG15 conjugation system was overexpressed, ISG15 was conjugated to RIG-I and cellular levels of the unconjugated form of RIG-I decreased. The ISGylation of RIG-I reduced levels of both basal and virus-induced IFN promoter activity. Levels of unconjugated RIG-I also decreased when 26S proteasome activity was blocked by treatment with MG132, ALLN, or Lactacystin. In the presence of MG132, ISG15 conjugation to RIG-I increased, and hence, the unconjugated form of RIG-I was reduced. In Ube1L–/– cells, which lack the ability to conjugate ISG15, basal levels of both RIG-I protein and transcripts were increased compared to those in wild-type cells. As a result, enhanced production of ISGs and enhanced IFN promoter activity in Ube1L–/– cells were observed, and the phenotype was restored to that of wild-type cells by the overexpression of Ube1L. Based on these results, we propose a novel negative feedback loop which adjusts the strength of the RIG-I-mediated antiviral response and IFN production through the regulation of RIG-I protein by IFN-induced ISG15 conjugation.

* Corresponding author. Mailing address: Department of Life Sciences, POSTECH, Pohang 790-784, Republic of Korea. Phone: 82-54-279-2346. Fax: 82-54-279-2199. E-mail: jyoo{at}postech.ac.kr

{triangledown} Published ahead of print on 5 December 2007.

Journal of Virology, February 2008, p. 1474-1483, Vol. 82, No. 3
0022-538X/08/$08.00+0     doi:10.1128/JVI.01650-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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