Calnexin Phosphorylation Attenuates the Release of Partially Misfolded α1-Antitrypsin to the Secretory Pathway

• Published in: The Journal of biological chemistry 2009-12, Vol.284 (50), p.34570
• Main Authors: Pamela H. Cameron, Eric Chevet, Olivier Pluquet, David Y. Thomas, John J. M. Bergeron
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.053165

Calnexin is a type I integral membrane phosphoprotein resident of the endoplasmic reticulum. Its intraluminal domain has been deduced to function as a lectin chaperone coordinating the timing of folding of newly synthesized N -linked glycoproteins of the secretory pathway. Its C-terminal cytosolic oriented extension has an ERK1 phosphorylation site at Ser 563 affecting calnexin association with the translocon. Here we find an additional function for calnexin phosphorylation at Ser 563 in endoplasmic reticulum quality control. A low dose of the misfolding agent l -azetidine 2-carboxylic acid slows glycoprotein maturation and diminishes the extent and rate of secretion of newly synthesized secretory α1-antitrypsin. Under these conditions the phosphorylation of calnexin is enhanced at Ser 563 . Inhibition of this phosphorylation by the MEK1 inhibitor PD98059 enhanced the extent and rate of α1-antitrypsin secretion comparable with that achieved by inhibiting α-mannosidase activity with kifunensine. This is the first report in which the phosphorylation of calnexin is linked to the efficiency of secretion of a cargo glycoprotein.