title: Monomerization and ER Relocalization of GRASP Is a Requisite for Unconventional Secretion of CFTR.
abstract: Induction of endoplasmic reticulum (ER)-to-Golgi blockade or ER stress induces Golgi reassembly stacking protein (GRASP)-mediated, Golgi-independent unconventional cell-surface trafficking of the folding-deficient ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR). However, molecular mechanisms underlying this process remain elusive. Here, we show that phosphorylation-dependent dissociation of GRASP homotypic complexes and subsequent relocalization of GRASP to the ER play a critical role in the unconventional secretion of CFTR. Immunolocalization analyses of mammalian cells revealed that the Golgi protein GRASP55 was redistributed to the ER by stimuli that induce unconventional secretion of ΔF508-CFTR, such as induction of ER-to-Golgi blockade by the Arf1 mutant. Notably, the same stimuli also induced phosphorylation of regions near the C-terminus of GRASP55 and dissociation of GRASP homomultimer complexes. Furthermore, phosphorylation-mimicking mutations of GRASP55 induced the monomerization and ER relocalization of GRASP55, and these changes were nullified by phosphorylation-inhibiting mutations. These results provide mechanistic insights into how GRASP accesses the ER-retained ΔF508-CFTR and mediates the ER stress-induced unconventional secretion pathway.
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Jiyoon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Shin Hye
authors.initials: SH
authors.lastname: Noh
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: He
authors.initials: H
authors.lastname: Piao
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Dong Hee
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul, 120-749, Korea.
authors.forename: Kuglae
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul, 120-749, Korea.
authors.forename: Jeong Seok
authors.initials: JS
authors.lastname: Cha
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Woo Young
authors.initials: WY
authors.lastname: Chung
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul, 120-749, Korea.
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D006056:Golgi Apparatus / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010957:Plasmids; D055503:Protein Multimerization; D021381:Protein Transport; D055571:Secretory Pathway; D014162:Transfection
chemical_list: C505032:CFTR protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; C410230:tamalin protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CFTR; ER stress; ER-to-Golgi blockade; GRASP; unconventional secretion