Abstract

ABSTRACT: The accumulation of unfolded proteins within the endoplasmic reticulum (ER) causes ER stress and
activation of unfolded protein response (UPR). This response can trigger ER-associated degradation and autophagy,
which clear unfolded proteins and restore protein homeostasis. Recently, it has become clear that ubiquitination
plays an important role in the regulation of autophagy. In the present study, we investigated how the E3 ubiquitin
ligase neural precursor cell–expressed, developmentally down-regulated protein 4-2 (Nedd4-2) interacts with ER
stress and autophagy. In mice, we found that an increase in the expression of Nedd4-2, which was concomitant with
the activation of the UPR and autophagy, was caused by a prolonged high-fructose and high-fat diet that induces ER
stress in the liver. Pharmacologic induction of ER stress also led to an increase inNedd4-2 expression in cultured cells,
which was coincident with UPR and autophagy activation. The inhibition of inositol-requiring enzyme 1 significantly
suppressed Nedd4-2 expression. Moreover, increased Nedd4-2 expression in vivo was closely associated with
the activation of inositol-requiring enzyme 1 and increasedexpression of the spliced form of X-box binding protein 1.
Furthermore, knockdown of Nedd4-2 in cultured cells suppressed both basal autophagy and ER stress–induced
autophagy, whereas overexpression of Nedd4-2–induced autophagy. Taken together, our findings provide evidence
that Nedd4-2 is up-regulated in response to ER stress by the spliced form of X-box binding protein 1 and that this is
important in the induction of an appropriate autophagic response.—Wang, H. Sun, R.-Q., Camera, D., Zeng, X.-Y.,
Jo, E., Chan, S. M. H., Herbert, T. P., Molero, J. C., Ye, J.-M. Endoplasmic reticulum stress up-regulates Nedd4-2 to
induce autophagy. FASEB J. 30, 2549–2556 (2016). www.fasebj.org