Sec16A is critical for both conventional and unconventional secretion of CFTR

Abstract

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.

Phospho-Rasputin Stabilization by Sec16 Is Required for Stress Granule Formation upon Amino Acid Starvation

“…Sec16 also plays key roles in the response to stress, for instance, to ER stress where it appears to mediate the Golgi bypass of transmembrane proteins (Piao et al, 2017), but also to nutrient stress (Zacharogianni et al, 2011). Amino acid starvation is an interesting stress as it triggers the formation of two stress assemblies in the same time frame, both requiring Sec16 but in two different manners: The first, the MARylation of Sec16 on its C terminus by ER-localized dPARP16, is an event that is enough to trigger the formation of Sec bodies (Aguilera-Gomez et al, 2016).…”

CHC22 clathrin mediates traffic from early secretory compartments for human GLUT4 pathway biogenesis

“…Identification of this sorting pathway for GLUT4 from the ERGIC to the GSC adds to the variety of sorting pathways that are known to emerge from the ERGIC, sustaining both conventional (ER to Golgi; Kondylis and Rabouille, 2003;Sohda et al, 2007) and unconventional (Golgi bypass) pathways for autophagy (Ge et al, 2013;Ge and Schekman, 2014) or cargo exocytosis (Piao et al, 2017). In humans, and even in CHC22 transgenic mice, CHC22 expression parallels that of GLUT4, with its highest expression in GLUT4-expressing tissues (Hoshino et al, 2013).…”

CHC22 clathrin mediates traffic from early secretory compartments for human GLUT4 pathway biogenesis

“…Identification of this sorting pathway for GLUT4 from the ERGIC to the GSC adds to the variety of sorting pathways that are known to emerge from the ERGIC, sustaining both conventional (ER-to-Golgi) (Kondylis and Rabouille, 2003;Sohda et al, 2007) and unconventional (Golgi bypass) pathways for autophagy (Ge et al, 2013;Ge and Schekman, 2014) or cargo exocytosis (Piao et al, 2017). Furthermore, our model for GLUT4 sorting to the GSC from the ERGIC is consistent with the reported ERGIC localization of the TUG protein involved in GLUT4 vesicle retention (Orme and Bogan, 2012) and with the recent finding that Sec16A is required for GSC formation.…”