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A role for mammalian Ubc6 homologues in ER-associated protein degradation

Uwe Lenk¹, Helen Yu^2,*, Jan Walter¹, Marina S. Gelman², Enno Hartmann³, Ron R. Kopito² and Thomas Sommer^1,

¹ The Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Str. 10, 13092 Berlin, Germany
² Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020, USA
³ Universität Lübeck, Institut für Biologie, Ratzeburger Allee 160, 23538 Lübeck, Germany
^* Present address: Odyssey Pharmaceuticals Inc., 4550 Norris Canyon Road, Suite 140, San Ramon, CA 94583, USA

Author for correspondence (e-mail: tsommer{at}mdc-berlin.de )

Accepted 10 May 2002

Integral membrane and secretory proteins which fail to fold productively are retained in the endoplasmic reticulum and targeted for degradation by cytoplasmic proteasomes. Genetic and biochemical analyses suggest that substrates of this pathway must be dislocated across the membrane of the endoplasmic reticulum (ER) by a process requiring a functional Sec61 complex and multiubiquitinylation. In yeast, the tail-anchored ubiquitin-conjugating enzyme Ubc6p, which is localized to the cytoplasmic surface of the ER, participates in ER-associated degradation (ERAD) of misfolded proteins. Here we describe the identification of two families of mammalian Ubc6p-related proteins. Members of both families are also located in the ER membrane and display a similar membrane topology as the yeast enzyme. Furthermore we show that expression of elevated levels of wild-type and dominant-negative alleles of these components affects specifically ERAD of the subunit of the T-cell receptor and a mutant form of the CFTR protein. Similarly, we describe that the expression level of Ubc6p in yeast is also critical for ERAD, suggesting that the Ubc6p function is highly conserved from yeast to mammals.

Key words: Endoplasmic reticulum, Ubiquitin, Proteolysis

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