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J. Biol. Chem., Vol. 281, Issue 45, 34064-34071, November 10, 2006

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Distinct Induction Patterns and Functions of Two Closely Related Interferon-inducible Human Genes, ISG54 and ISG56^*

Fulvia Terenzi, Daniel J. Hui, William C. Merrick, and Ganes C. Sen¹

From the Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195 and the Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

Human P54 and P56 proteins are tetratricopeptide proteins that are encoded by two closely related genes, ISG54 and ISG56. These genes are induced strongly but transiently when cells are treated with interferons or double-stranded RNA or infected with a variety of viruses. We observed that, although double-stranded RNA or Sendai virus infection induced the two genes with similar kinetics, their induction kinetics in response to interferon- were quite different. The induction kinetics by virus infection were also different between two cell lines. Functionally the two proteins were similar. Like P56, P54 bound to the translation initiation factor eIF3 and inhibited translation. However, unlike P56, P54 bound to both the "e" and the "c" subunits of eIF3. Consequently, P54 inhibited two functions of eIF3. Like P56, it inhibited the ability of eIF3 to stabilize the eIF2·GTP·Met-tRNA_i ternary complex. But in addition, it also inhibited the formation of the 48 S pre-initiation complex between the 40 S ribosomal subunit and the 20 S complex composed of eIF3, ternary complex, eIF4F, and mRNA. Thus, although similar in structure, the human P54 and P56 proteins are induced differently and function differently.

Received for publication, June 15, 2006 , and in revised form, August 17, 2006.

^* This work was supported by National Institutes of Health Grants CA68782 and CA62220. 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: Dept. of Molecular Genetics/NE20 Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-444-0636; Fax: 216-444-0513; E-mail: seng{at}ccf.org.

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