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Molecular and Cellular Biology, May 2005, p. 3483-3491, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3483-3491.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

FAT10, a Ubiquitin-Independent Signal for Proteasomal Degradation

Mark Steffen Hipp,{dagger} Birte Kalveram,{dagger} Shahri Raasi,{ddagger} Marcus Groettrup,* and Gunter Schmidtke

Division of Immunology, Department of Biology, University of Constance, D-78457 Konstanz, Germany

Received 18 October 2004/ Returned for modification 3 February 2005/ Accepted 14 February 2005

FAT10 is a small ubiquitin-like modifier that is encoded in the major histocompatibility complex and is synergistically inducible by tumor necrosis factor alpha and gamma interferon. It is composed of two ubiquitin-like domains and possesses a free C-terminal diglycine motif that is required for the formation of FAT10 conjugates. Here we show that unconjugated FAT10 and a FAT10 conjugate were rapidly degraded by the proteasome at a similar rate. Fusion of FAT10 to the N terminus of very long-lived proteins enhanced their degradation rate as potently as fusion with ubiquitin did. FAT10-green fluorescent protein fusion proteins were not cleaved but entirely degraded, suggesting that FAT10-specific deconjugating enzymes were not present in the analyzed cell lines. Interestingly, the prevention of ubiquitylation of FAT10 by mutation of all lysines or by expression in ubiquitylation-deficient cells did not affect FAT10 degradation. Thus, conjugation with FAT10 is an alternative and ubiquitin-independent targeting mechanism for degradation by the proteasome, which, in contrast to polyubiquitylation, is cytokine inducible and irreversible.

* Corresponding author. Mailing address: Universität Konstanz, Fachbereich Biologie/Immunologie, P1101, Universitätsstrasse 10, D-78457 Konstanz, Germany. Phone: 49 7531 882130. Fax: 49 7531 883102. E-mail: Marcus.Groettrup{at}uni-konstanz.de.

{dagger} These authors contributed equally to this work and are both considered first authors.

{ddagger} Present address: Department of Biochemistry and Molecular Biology, School of Public Health, Johns Hopkins University, Baltimore, MD 21205.

Molecular and Cellular Biology, May 2005, p. 3483-3491, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3483-3491.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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