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MBC in Press, published online ahead of print February 20, 2004
Mol. Biol. Cell 10.1091/mbc.E03-12-0899

A more recent version of this article appeared on May 1, 2004
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Submitted on December 17, 2003
Revised on January 18, 2004
Accepted on January 26, 2004

Separate Roles and Different Routing of Calnexin and ERp57 in ER Quality Control Revealed by Interactions with Asialoglycoprotein Receptor Chains

Zehavit Frenkel1, Marina Shenkman1, Maria Kondratyev1, and Gerardo Z. Lederkremer1*

1 Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel

* Corresponding author. E-mail address: gerardo{at}post.tau.ac.il.

The thiol oxidoreductase ERp57 interacts with newly synthesized glycoproteins through ternary complexes with the chaperones/lectins calnexin or calreticulin. On proteasomal inhibition calnexin and calreticulin concentrate in the pericentriolar ER-derived Quality Control compartment (ERQC) that we recently described. Surprisingly, ERp57 remained in an endoplasmic reticulum pattern. Using asialoglycoprotein receptor H2a and H2b as models we determined in pulse-chase experiments that both glycoproteins initially bind to calnexin and ERp57. However, H2b, which will exit to the Golgi, dissociated from calnexin and remained bound for a longer period to ERp57 whereas the opposite was true for the endoplasmic reticulum-associated degradation (ERAD) substrate H2a, that will go to the ERQC. At 15°C ERp57 colocalized with H2b adjacent to an ER-Golgi intermediate compartment (ERGIC) marker. Posttranslational inhibition of glucose excision prolonged association of H2a precursor to calnexin but not to ERp57. Preincubation with a low concentration (15 µg/ml) of the glucosidase inhibitor castanospermine prevented the association of H2a to ERp57 but not to calnexin. This low concentration of castanospermine accelerated the degradation of H2a, suggesting that ERp57 protects the glycoprotein from degradation and not calnexin. Our results suggest an early chaperone-mediated sorting event with calnexin being involved in the quality control retention of molecules bound for ERAD and ERp57 giving initial protection from degradation and later assisting the maturation of molecules that will exit to the Golgi.






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