Calnexin phosphorylation attenuates the release of partially misfolded alpha1-antitrypsin to the secretory pathway.
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 alpha1-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 alpha1-antitrypsin secretion comparable with that achieved by inhibiting alpha-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.
Cameron
Pamela H
PH
Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 2B2, Canada.
Chevet
Eric
E
Pluquet
Olivier
O
Thomas
David Y
DY
Bergeron
John J M
JJ
D000470:Alkaloids / Q000378:metabolism; D000818:Animals; D037281:Calnexin / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000378:metabolism; D005419:Flavonoids / Q000378:metabolism; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D017510:Protein Folding; D055571:Secretory Pathway / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D000470:Alkaloids; D004791:Enzyme Inhibitors; D005419:Flavonoids; D000515:alpha 1-Antitrypsin; C065629:kifunensine; D037281:Calnexin; D012694:Serine; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one