Palmitoylated calnexin is a key component of the ribosome-translocon complex.
A third of the human genome encodes N-glycosylated proteins. These are co-translationally translocated into the lumen/membrane of the endoplasmic reticulum (ER) where they fold and assemble before they are transported to their final destination. Here, we show that calnexin, a major ER chaperone involved in glycoprotein folding is palmitoylated and that this modification is mediated by the ER palmitoyltransferase DHHC6. This modification leads to the preferential localization of calnexin to the perinuclear rough ER, at the expense of ER tubules. Moreover, palmitoylation mediates the association of calnexin with the ribosome-translocon complex (RTC) leading to the formation of a supercomplex that recruits the actin cytoskeleton, leading to further stabilization of the assembly. When formation of the calnexin-RTC supercomplex was affected by DHHC6 silencing, mutation of calnexin palmitoylation sites or actin depolymerization, folding of glycoproteins was impaired. Our findings thus show that calnexin is a stable component of the RTC in a manner that is exquisitely dependent on its palmitoylation status. This association is essential for the chaperone to capture its client proteins as they emerge from the translocon, acquire their N-linked glycans and initiate folding.
Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Asvin Kk
AK
Lakkaraju
Laurence
L
Abrami
Thomas
T
Lemmin
Sanja
S
Blaskovic
Béatrice
B
Kunz
Akio
A
Kihara
Matteo
M
Dal Peraro
Françoise Gisou
FG
van der Goot
D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D037281:Calnexin / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D020868:Gene Silencing; D006023:Glycoproteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D054878:Lipoylation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018000:Receptors, Peptide / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D018000:Receptors, Peptide; C572507:ZDHHC6 protein, human; C066973:signal sequence receptor; D037281:Calnexin; D000217:Acyltransferases