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Vol. 11, Issue 10, 3559-3572, October 2000
and§
¶
*Department of Physiology and Biophysics, Animal cell viruses provide valuable model systems for studying
many normal cellular processes, including membrane protein sorting. The
focus of this study is an integral membrane protein encoded by the E3
transcription region of human adenoviruses called E3-13.7, which
diverts recycling EGF receptors to lysosomes without increasing the
rate of receptor internalization or intrinsic receptor tyrosine kinase
activity. Although E3-13.7 can be found on the plasma membrane when it
is overexpressed, its effect on EGF receptor trafficking suggests that
the plasma membrane is not its primary site of action. Using cell
fractionation and immunocytochemical experimental approaches, we now
report that the viral protein is located predominantly in early
endosomes and limiting membranes of endosome-to-lysosome transport
intermediates called multivesicular endosomes. We also demonstrate that
E3-13.7 physically associates with EGF receptors undergoing
E3-13.7-mediated down-regulation in early endosomes. Receptor-viral
protein complexes then dissociate, and EGF receptors proceed to
lysosomes, where they are degraded, while E3-13.7 is retained in
endosomes. We conclude that E3-13.7 is a resident early endocytic
protein independent of EGF receptor expression, because it has
identical intracellular localization in mouse cells lacking endogenous
receptors and cells expressing a human cytomegalovirus-driven receptor
cDNA. Finally, we demonstrate that EGF receptor residues 675-697 are
required for E3-13.7-mediated down-regulation. Interestingly, this
sequence includes a known EGF receptor leucine-based lysosomal sorting
signal used during ligand-induced trafficking, which is also conserved
in the viral protein. E3-13.7, therefore, provides a novel model system
for determining the molecular basis of selective membrane protein transport in the endocytic pathway. Our studies also suggest new paradigms for understanding EGF receptor sorting in endosomes and
adenovirus pathogenesis.
Molecular
Virology Training Program, and §Case Western Reserve
University Cancer Center, School of Medicine, Case Western Reserve
University, Cleveland, Ohio 44106; The Rainbow Center
for Childhood Polycystic Kidney Disease at Rainbow Babies and
Children's Hospital of Cleveland, Cleveland, Ohio 44106; and
Integrated Imaging Center, Department of Biology, Johns
Hopkins University, Baltimore, Maryland 21218
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