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J. Biol. Chem., Vol. 275, Issue 31, 23491-23499, August 4, 2000
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From the The latent membrane protein 1 (LMP1) of the
Epstein-Barr virus is a constitutively active receptor essential for B
lymphocyte transformation by the Epstein-Barr virus. It is a
short-lived protein, but the proteolytic pathway involved in its
degradation is not known. The ubiquitin pathway is a major system for
specific protein degradation in eukaryotes. Most plasma membrane
substrates of the pathway are internalized upon ubiquitination and
delivered for degradation in the lysosome/vacuole. Here we show that
LMP1 is a substrate of the ubiquitin pathway and is ubiquitinated both in vitro and in vivo. However, in contrast to
other plasma membrane substrates of the ubiquitin system, it is
degraded mostly by the proteasome and not by lysosomes. Degradation is
independent of the single Lys residue of the protein; a lysine-less
mutant LMP1 is degraded in a ubiquitin- and
proteasome-dependent manner similar to the wild type
protein. Degradation of both wild type and lysine-less protein is
sensitive to fusion of a Myc tag to the N terminus of LMP1. In
addition, deletion of as few as 12 N-terminal amino acid residues
stabilizes the protein. These findings suggest that the first event in
LMP1 degradation is attachment of ubiquitin to the N-terminal residue
of the protein. We present evidence suggesting that phosphorylation is
also required for degradation of LMP1.
Degradation of the Epstein-Barr Virus Latent Membrane Protein
1 (LMP1) by the Ubiquitin-Proteasome Pathway
TARGETING VIA UBIQUITINATION OF THE N-TERMINAL RESIDUE*
§,
,
Department of Biochemistry and the Rappaport
Family Institute for Research in the Medical Sciences, The Bruce
Rappaport Faculty of Medicine, Technion-Israel Institute of Technology,
Haifa 31096, Israel and the ¶ Microbiology and Tumor Biology
Center, Karolinska Institute, Stockholm S-171 77, Sweden
*
This work was supported by grants from the Israel Science
Foundation founded by the Israeli Academy of Sciences and Humanities, Centers of Excellence Program, the German-Israeli Foundation for Scientific Research and Development, the U.S.-Israel Binational Science
Foundation, the German-Israeli Cooperation Project, the Israel Cancer
Society, the Foundation for Promotion of Research at the Technion, a
research grant administered by the Vice President of the Technion for
Research (to A. C.), and a Training and Mobility of Researchers
(TMR) grant from the European Community (to A. C. and M. M.).
Purchasing of the ABI 310 autosequencer was supported partially by a
grant from the Israel Science Foundation founded by the Israeli Academy
of Sciences and Humanities.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.
Supported by a grant from the Swedish Medical Research Council.
**
Supported by grants from the Swedish Cancer Society and the Swedish
Foundation for Strategic Research.
To whom correspondence should be addressed: Dept. of
Biochemistry, Faculty of Medicine, Technion-Israel Institute of
Technology, P.O. Box 9649, Haifa 31096, Israel. E-mail:
mdaaron@tx.technion.ac.il.
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