Fig. 10

Schematic illustration of a proposed model for how AGR2 controls the release of 14-3-3ε and α-actinin 4 to promote chemotaxis of CMT cells. AGR2 functions as a stress sensor, regulating proteostasis by controlling the release of unconventional secretory proteins. Upon serum starvation, tunicamycin-induced ER stress, or rapamycin-induced autophagy, AGR2 expression promotes the release of 14-3-3ε and α-actinin 4 into the extracellular microenvironment, thereby enhancing chemotaxis in CMT cells. This controlled release of 14-3-3ε and α-actinin 4 by AGR2 involves extracellular vesicle (EV)-mediated delivery and secretory autophagy. Depletion of AGR2 leads to a reduced release of 14-3-3ε and α-actinin 4 in response to serum starvation, ER stress, or autophagy induction. Additionally, the absence of AGR2 can result in diminished uptake of 14-3-3ε within the LC3B⁺ autophagosome and impaired export of α-actinin 4 through the LC3B⁺ autophagosome