ERp18 regulates activation of ATF6? during unfolded protein response

Activation of the ATF6? signalling pathway is initiated by trafficking of ATF6? from the ER to the Golgi apparatus. Its subsequent proteolysis releases a transcription factor that translocates to the nucleus causing downstream gene activation. How ER retention, Golgi trafficking and proteolysis of ATF6? are regulated and if additional protein partners are required for its localization and processing remains unresolved. Here, we show that ER-resident oxidoreductase ERp18 associates with ATF6? following ER stress and plays a key role in both trafficking and activation of ATF6?. We find that ERp18 depletion attenuates the ATF6? stress response. Paradoxically, ER stress accelerates trafficking of ATF6? to the Golgi in ERp18-depleted cells. However, the translocated ATF6? becomes aberrantly processed preventing release of the soluble transcription factor. Hence, we demonstrate that ERp18 monitors ATF6? ER quality control to ensure optimal processing following trafficking to the Golgi.