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 and Min Goo Lee
Version of Record online: 18 MAY 2016 | DOI: 10.1111/tra.12403
Endoplasmic reticulum (ER)-to-Golgi blockade or ER stress induces Golgi reassembly stacking protein (GRASP)-mediated, Golgi-bypassing cell-surface trafficking of the folding-deficient ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR). Here, we show the mechanism by which the Golgi protein GRASP accesses the ER-retained ΔF508-CFTR, which may offer insights toward therapeutic strategies for cystic fibrosis. ER stress-associated signals induce phosphorylation-dependent dissociation of GRASP55 complexes and significant amounts of disassembled GRASP55 undergo relocalization into the ER. Migration of GRASP55 to the ER enables the association with ΔF508-CFTR via a PSD95/Dlg1/ZO-1-based interaction and subsequent unconventional surface trafficking of CFTR.