title: Palmitoylation is the switch that assigns calnexin to quality control or ER Ca2+ signaling.
abstract: The palmitoylation of calnexin serves to enrich calnexin on the mitochondria-associated membrane (MAM). Given a lack of information on the significance of this finding, we have investigated how this endoplasmic reticulum (ER)-internal sorting signal affects the functions of calnexin. Our results demonstrate that palmitoylated calnexin interacts with sarcoendoplasmic reticulum (SR) Ca(2+) transport ATPase (SERCA) 2b and that this interaction determines ER Ca(2+) content and the regulation of ER-mitochondria Ca(2+) crosstalk. In contrast, non-palmitoylated calnexin interacts with the oxidoreductase ERp57 and performs its well-known function in quality control. Interestingly, our results also show that calnexin palmitoylation is an ER-stress-dependent mechanism. Following a short-term ER stress, calnexin quickly becomes less palmitoylated, which shifts its function from the regulation of Ca(2+) signaling towards chaperoning and quality control of known substrates. These changes also correlate with a preferential distribution of calnexin to the MAM under resting conditions, or the rough ER and ER quality control compartment (ERQC) following ER stress. Our results have therefore identified the switch that assigns calnexin either to Ca(2+) signaling or to protein chaperoning.
authors.affiliation: Department of Cell Biology, University of Alberta, Edmonton, AB T6G 2H7, Canada.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Lynes
authors.forename: Arun
authors.initials: A
authors.lastname: Raturi
authors.forename: Marina
authors.initials: M
authors.lastname: Shenkman
authors.forename: Carolina
authors.initials: C
authors.lastname: Ortiz Sandoval
authors.forename: Megan C
authors.initials: MC
authors.lastname: Yap
authors.forename: Jiahui
authors.initials: J
authors.lastname: Wu
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Janowicz
authors.forename: Nathan
authors.initials: N
authors.lastname: Myhill
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Benson
authors.forename: Robert E
authors.initials: RE
authors.lastname: Campbell
authors.forename: Luc G
authors.initials: LG
authors.lastname: Berthiaume
authors.forename: Gerardo Z
authors.initials: GZ
authors.lastname: Lederkremer
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmen
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D037281:Calnexin / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005347:Fibroblasts; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D054878:Lipoylation / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*
chemical_list: D037281:Calnexin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human; C506946:ATP2A2 protein, human; D002118:Calcium
keywords: Ca2+ signaling; ERp57; Endoplasmic reticulum; Mitochondria; Quality control; SERCA2b