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Monomerization and ER Relocalization of GRASP Is a Requisite for Unconventional Secretion of CFTR

 Jiyoon Kim  ;  Shin Hye Noh  ;  He Piao  ;  Dong Hee Kim  ;  Kuglae Kim  ;  Jeong Seok Cha  ;  Woo Young Chung  ;  Hyun-Soo Cho  ;  Joo Young Kim  ;  Min Goo Lee 
 TRAFFIC, Vol.17(7) : 733-753, 2016 
Journal Title
Issue Date
Carrier Proteins/genetics ; Carrier Proteins/metabolism* ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/secretion* ; Endoplasmic Reticulum/metabolism* ; Endoplasmic Reticulum Stress ; Golgi Apparatus/metabolism* ; HEK293 Cells ; HeLa Cells ; Humans ; Membrane Proteins/genetics ; Membrane Proteins/metabolism* ; Mutation ; Plasmids ; Protein Multimerization ; Protein Transport ; Secretory Pathway* ; Transfection
CFTR ; ER stress ; ER-to-Golgi blockade ; GRASP ; unconventional secretion
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.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Dong Hee(김동희)
Kim, Joo Young(김주영) ORCID logo https://orcid.org/0000-0003-2623-1491
Kim, Ji Yoon(김지윤)
Noh, Shin Hye(노신혜)
Piao He(박학) ORCID logo https://orcid.org/0000-0002-1817-3167
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
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