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J Biol Chem, Vol. 273, Issue 45, 29873-29878, November 6, 1998
and a Cytosolic, Deglycosylated
Intermediary
§,
, and§¶
From the Departments of Endoplasmic reticulum (ER)
degradation pathways can selectively route proteins away from folding
and maturation. Both soluble and integral membrane proteins can be
targeted from the ER to proteasomal degradation in this fashion. The
cystic fibrosis transmembrane conductance regulator (CFTR) is an
integral, multidomain membrane protein localized to the apical surface
of epithelial cells that functions to facilitate Cl Medicine, Cell
Biology, and ¶ Physiology and Biophysics and § Gregory
Fleming James Cystic Fibrosis Research Center, University of Alabama at
Birmingham, Birmingham, Alabama 35294
transport. CFTR was among the first membrane proteins for which a role
of the proteasome in ER-related degradation was described. However, the
signals that route CFTR to ubiquitination and subsequent degradation
are not known. Moreover, limited information is available concerning
the subcellular localization of polyubiquitinated CFTR or mechanisms
underlying retrograde dislocation of CFTR from the ER membrane to the
proteasome either before or after ubiquitination. In the present study,
we show that proteasome inhibition with clasto-lactacystin
-lactone (4 µM, 1 h) stabilizes the presence of a
deglycosylated CFTR intermediate for up to 5 h without increasing the core glycosylated (band B) form of CFTR. Deglycosylated CFTR is
present under the same conditions that result in accumulation of
polyubiquitinated CFTR. Moreover, the deglycosylated form of both wild
type and 
F508 CFTR can be found in the cytosolic fraction. Both the
level and stability of cytosolic, deglycosylated CFTR are increased by
proteasome blockade. During retrograde translocation from the ER to the
cytosol, CFTR associates with the Sec61 trimeric complex. Sec61 is the
key component of the mammalian co-translational protein
translocation system and has been proposed to function as a two way
channel that transports proteins both into the ER and back to the
cytosol for degradation. We show that the level of the Sec61·CFTR
complexes are highest when CFTR degradation proceeds at the greatest
rate (approximately 90 min after pulse labeling). Quantities of
Sec61·CFTR complexes are also increased by inhibition of the
proteasome. Based on these results, we propose a model in which complex
membrane proteins such as CFTR are transported through the Sec61
trimeric complex back to the cytosol, escorted by the subunit
of Sec61, and degraded by the proteasome or by other proteolytic systems.
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