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

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)733-753
Number of pages21
JournalTraffic
Volume17
Issue number7
DOIs
Publication statusPublished - 2016 Jul 1

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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    Kim, J., Noh, S. H., Piao, H., Kim, D. H., Kim, K., Cha, J. S., Chung, W. Y., Cho, H. S., Kim, J. Y., & Lee, M. G. (2016). Monomerization and ER Relocalization of GRASP Is a Requisite for Unconventional Secretion of CFTR. Traffic, 17(7), 733-753. https://doi.org/10.1111/tra.12403