Sec16A is critical for both conventional and unconventional secretion of CFTR

• Published in: Scientific reports Vol. 7; no. 1; p. 39887
• Main Authors: Piao, He, Kim, Jiyoon, Noh, Shin Hye, Kweon, Hee-Seok, Kim, Joo Young, Lee, Min Goo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-01-2017; Nature Publishing Group
• Subjects: 13/1; 13/109; 14; 14/19; 14/28; 14/35; 38; 631/80/2023; 631/80/313/2376; 82; 82/29; Cell surface; Cystic fibrosis; Gene silencing; Golgi apparatus; Humanities and Social Sciences; Mammalian cells; Mammals; Morphology; multidisciplinary; Mutation; Plasma; Proteins; Science; Secretion
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep39887

CFTR is a transmembrane protein that reaches the cell surface via the conventional Golgi mediated secretion pathway. Interestingly, ER-to-Golgi blockade or ER stress induces alternative GRASP-mediated, Golgi-bypassing unconventional trafficking of wild-type CFTR and the disease-causing ΔF508-CFTR, which has folding and trafficking defects. Here, we show that Sec16A, the key regulator of conventional ER-to-Golgi transport, plays a critical role in the ER exit of protein cargos during unconventional secretion. In an initial gene silencing screen, Sec16A knockdown abolished the unconventional secretion of wild-type and ΔF508-CFTR induced by ER-to-Golgi blockade, whereas the knockdown of other COPII-related components did not. Notably, during unconventional secretion, Sec16A was redistributed to cell periphery and associated with GRASP55 in mammalian cells. Molecular and morphological analyses revealed that IRE1α-mediated signaling is an upstream regulator of Sec16A during ER-to-Golgi blockade or ER stress associated unconventional secretion. These findings highlight a novel function of Sec16A as an essential mediator of ER stress-associated unconventional secretion.