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J. Cell Biol.,
Volume 142, Number 1, July 13, 1998 51-57
Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9038
The composition of the plasma membrane
domains of epithelial cells is maintained by biosynthetic
pathways that can sort both proteins and lipids into
transport vesicles destined for either the apical or basolateral surface. In MDCK cells, the influenza virus hemagglutinin is sorted in the trans-Golgi network into detergent-insoluble, glycosphingolipid-enriched membrane domains that are proposed to be necessary for
sorting hemagglutinin to the apical cell surface. Site-
directed mutagenesis of the hemagglutinin transmembrane domain was used to test this proposal. The region of the transmembrane domain required for apical
transport included the residues most conserved among
hemagglutinin subtypes. Several mutants were found to
enter detergent-insoluble membranes but were not
properly sorted. Replacement of transmembrane residues 520 and 521 with alanines converted the 2A520
mutant hemagglutinin into a basolateral protein. Depleting cell cholesterol reduced the ability of wild-type
hemagglutinin to partition into detergent-insoluble membranes but had no effect on apical or basolateral
sorting. In contrast, cholesterol depletion allowed random transport of the 2A520 mutant. The mutant appeared to lack sorting information but was prevented
from reaching the apical surface when detergent-insoluble membranes were present. Apical sorting of hemagglutinin may require binding of either protein or
lipids at the middle of the transmembrane domain and
this normally occurs in detergent-insoluble membrane domains. Entry into these domains appears necessary,
but not sufficient, for apical sorting.
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