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Vol. 15, Issue 5, 2133-2142, May 2004

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

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

Submitted December 17, 2003; Revised January 18, 2004; Accepted January 26, 2004
Monitoring Editor: Reid Gilmore

The thiol oxidoreductase endoplasmic reticulum (ER)p57 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 endoplasmic reticulum-derived quality control compartment 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 substrate H2a that will go to the endoplasmic reticulum-derived quality control compartment. At 15°C, ERp57 colocalized with H2b adjacent to an endoplasmic reticulum-Golgi intermediate compartment 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 endoplasmic reticulum-associated degradation and ERp57 giving initial protection from degradation and later assisting the maturation of molecules that will exit to the Golgi.

Abbreviations used: ASGPR, asialoglycoprotein receptor; CNX, calnexin; CRT, calreticulin; CST, castanospermine; DSP, 3,3' dithiobis sulfosuccimidylpropionate; ERAD, endoplasmic reticulum-associated degradation; ERGIC, endoplasmic reticulum-Golgi intermediate compartment; ERQC, endoplasmic reticulum-derived quality control compartment Glc, glucose; IP, immunoprecipitation; Lac, lactacystin; MG-132, N-carbobenzoxyl-leucinyl-leucinyl-leucinal.

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

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