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Vol. 12, Issue 5, 1303-1314, May 2001
and
*Department of Biological Sciences, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260; Membrane and secretory proteins fold in the endoplasmic reticulum
(ER), and misfolded proteins may be retained and targeted for
ER-associated protein degradation (ERAD). To elucidate the mechanism by
which an integral membrane protein in the ER is degraded, we studied
the fate of the cystic fibrosis transmembrane conductance regulator
(CFTR) in the yeast Saccharomyces cerevisiae. Our data indicate that CFTR resides in the ER and is stabilized in strains defective for proteasome activity or deleted for the
ubiquitin-conjugating enzymes Ubc6p and Ubc7p, thus demonstrating that
CFTR is a bona fide ERAD substrate in yeast. We also found that heat
shock protein 70 (Hsp70), although not required for the degradation of
soluble lumenal ERAD substrates, is required to facilitate CFTR
turnover. Conversely, calnexin and binding protein (BiP), which are
required for the proteolysis of ER lumenal proteins in both yeast and
mammals, are dispensable for the degradation of CFTR, suggesting unique mechanisms for the disposal of at least some soluble and integral membrane ERAD substrates in yeast.
Department of Cell
Biology and Anatomy, The Johns Hopkins University School of Medicine,
Baltimore, Maryland 21205; University of Pittsburgh
Biological Images Facility, University of Pittsburgh, Pittsburgh,
Pennsylvania 15261; and §Department of Biology, University
of Nevada, Reno, Nevada 89557
Corresponding author. E-mail:
jbrodsky+{at}pitt.edu.
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