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Molecular and Cellular Biology, December 2001, p. 8007-8021, Vol. 21, No. 23
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.23.8007-8021.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Construction and Analysis of Mouse Strains Lacking the Ubiquitin Ligase UBR1 (E3alpha ) of the N-End Rule Pathway

Yong Tae Kwon,1 Zanxian Xia,1 Ilia V. Davydov,1,dagger Stewart H. Lecker,2 and Alexander Varshavsky1,*

Division of Biology, California Institute of Technology, Pasadena, California 91125,1 and Renal Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts 021152

Received 6 June 2001/Accepted 6 September 2001

The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. In the yeast Saccharomyces cerevisiae, the UBR1-encoded ubiquitin ligase (E3) of the N-end rule pathway mediates the targeting of substrate proteins in part through binding to their destabilizing N-terminal residues. The functions of the yeast N-end rule pathway include fidelity of chromosome segregation and the regulation of peptide import. Our previous work described the cloning of cDNA and a gene encoding the 200-kDa mouse UBR1 (E3alpha ). Here we show that mouse UBR1, in the presence of a cognate mouse ubiquitin-conjugating (E2) enzyme, can rescue the N-end rule pathway in ubr1Delta S. cerevisiae. We also constructed UBR1-/- mouse strains that lacked the UBR1 protein. UBR1-/- mice were viable and fertile but weighed significantly less than congenic +/+ mice. The decreased mass of UBR1-/- mice stemmed at least in part from smaller amounts of the skeletal muscle and adipose tissues. The skeletal muscle of UBR1-/- mice apparently lacked the N-end rule pathway and exhibited abnormal regulation of fatty acid synthase upon starvation. By contrast, and despite the absence of the UBR1 protein, UBR1-/- fibroblasts contained the N-end rule pathway. Thus, UBR1-/- mice are mosaics in regard to the activity of this pathway, owing to differential expression of proteins that can substitute for the ubiquitin ligase UBR1 (E3alpha ). We consider these UBR1-like proteins and discuss the functions of the mammalian N-end rule pathway.

* Corresponding author. Mailing address: Division of Biology, 147-75, Caltech, 1200 East California Blvd., Pasadena, CA 91125. Phone: (626) 395-3785. Fax: (626) 440-9821. E-mail: avarsh{at}caltech.edu.

dagger Present address: IGEN International, Inc., Gaithersburg, MD 20877.

Molecular and Cellular Biology, December 2001, p. 8007-8021, Vol. 21, No. 23
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.23.8007-8021.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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