title: Palmitoylated TMX and calnexin target to the mitochondria-associated membrane.
abstract: The mitochondria-associated membrane (MAM) is a domain of the endoplasmic reticulum (ER) that mediates the exchange of ions, lipids and metabolites between the ER and mitochondria. ER chaperones and oxidoreductases are critical components of the MAM. However, the localization motifs and mechanisms for most MAM proteins have remained elusive. Using two highly related ER oxidoreductases as a model system, we now show that palmitoylation enriches ER-localized proteins on the MAM. We demonstrate that palmitoylation of cysteine residue(s) adjacent to the membrane-spanning domain promotes MAM enrichment of the transmembrane thioredoxin family protein TMX. In addition to TMX, our results also show that calnexin shuttles between the rough ER and the MAM depending on its palmitoylation status. Mutation of the TMX and calnexin palmitoylation sites and chemical interference with palmitoylation disrupt their MAM enrichment. Since ER-localized heme oxygenase-1, but not cytosolic GRP75 require palmitoylation to reside on the MAM, our findings identify palmitoylation as key for MAM enrichment of ER membrane proteins.
authors: Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors: Emily M
authors: EM
authors: Lynes
authors: Michael
authors: M
authors: Bui
authors: Megan C
authors: MC
authors: Yap
authors: Matthew D
authors: MD
authors: Benson
authors: Bobbie
authors: B
authors: Schneider
authors: Lars
authors: L
authors: Ellgaard
authors: Luc G
authors: LG
authors: Berthiaume
authors: Thomas
authors: T
authors: Simmen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D037281:Calnexin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003545:Cysteine / Q000378:metabolism; D004285:Dogs; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006367:HeLa Cells; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D054878:Lipoylation; D008545:Melanoma / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011490:Protein Disulfide Reductase (Glutathione) / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C425307:TMX1 protein, human; C478605:TMX2 protein, human; D037281:Calnexin; D013879:Thioredoxins; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D011490:Protein Disulfide Reductase (Glutathione); C546436:TMX4 protein, human; D019704:Protein Disulfide-Isomerases; C498879:TMX3 protein, human; D003545:Cysteine