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Vol. 8, Issue 10, 1943-1954, October 1997
and
Department of Cell Biology, Yale University School of Medicine, New
Haven, Connecticut 06510-8002
Unlike properly folded and assembled proteins, most misfolded and
incompletely assembled proteins are retained in the endoplasmic reticulum of mammalian cells and degraded without transport to the
Golgi complex. To analyze the mechanisms underlying this unique sorting
process and its fidelity, the fate of C-terminally truncated fragments
of influenza hemagglutinin was determined. An assortment of different
fragments was generated by adding puromycin at low concentrations to
influenza virus-infected tissue culture cells. Of the fragments
generated, <2% was secreted, indicating that the system for detecting
defects in newly synthesized proteins is quite stringent. The majority
of secreted species corresponded to folding domains within the viral
spike glycoprotein. The retained fragments acquired a partially folded
structure with intrachain disulfide bonds and conformation-dependent
antigenic epitopes. They associated with two lectin-like endoplasmic
reticulum chaperones (calnexin and calreticulin) but not BiP/GRP78.
Inhibition of the association with calnexin and calreticulin by the
addition of castanospermine significantly increased fragment secretion.
However, it also caused association with BiP/GRP78. These results
indicated that the association with calnexin and calreticulin was
involved in retaining the fragments. They also suggested that BiP/GRP78 could serve as a backup for calnexin and calreticulin in retaining the
fragments. In summary, the results showed that the quality control
system in the secretory pathway was efficient and sensitive to folding
defects, and that it involved multiple interactions with endoplasmic
reticulum chaperones.
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