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Originally published In Press as doi:10.1074/jbc.M205547200 on August 5, 2002

J. Biol. Chem., Vol. 277, Issue 41, 38818-38826, October 11, 2002
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Fusion Proteins with COOH-terminal Ubiquitin Are Stable and Maintain Dual Functionality in Vivo*

Shu-Bing QianDagger , David E. Ott§, Ulrich SchubertDagger , Jack R. BenninkDagger , and Jonathan W. YewdellDagger

From the Dagger  Laboratory of Viral Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892-0440 and § AIDS Vaccine Program, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702-1201

The ubiquitin (Ub) fusion degradation pathway functions to degrade fusion proteins containing a nonremovable Ub moiety at their NH2 terminus (Johnson, E. S., Ma, P. C., Ota, I. M., and Varshavsky, A. (1995) J. Biol. Chem. 270, 17442-17456). Here we show that ubiquitin fusion degradation also targets proteins for proteasomal degradation when Ub is present in the middle of fusion proteins (X-Ub-Y), in a process that entails polyubiquitylation of Ub Lys48. By contrast, fusion proteins bearing COOH-terminal Ub (X-Ub) are metabolically stable. Such fusion proteins, either newly biosynthesized or generated by Ub hydrolases, are reversibly conjugated to heterogeneous target proteins in a manner similar to wild-type Ub. Most importantly, the NH2-terminal fusion partner (X) can maintain its structure and function in the formed X-Ub conjugates as inferred from the fluorescence of green fluorescent protein-Ub conjugates and the incorporation of human immunodeficiency virus type 1 Gag-Ub into viral particles. These findings strongly suggest that 26S proteasomes exhibit spatial discrimination of Ub-conjugated proteins, sparing domains extended from the NH2 terminus of Ub from unfolding and degradation. The multifunctionality of X-Ub fusion proteins opens the possibility for a number of novel practical applications, including the imaging of Ub conjugate formation in living cells.

* This work has been funded in part by federal funds from the NCI, National Institutes of Health, under Contract No. NO1-CO-12400.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed: Laboratory of Viral Diseases, NIAID, National Institutes of Health, Rm. 205, Bldg. 4, 4 Center Dr., Bethesda, MD 20892-0440. Tel.: 301-402-4602; Fax: 301-402-7362; E-mail: jbennink@nih.gov (J. R. B.) or jyewdell{at}nih.gov (J. W. Y.).

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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