ERp18 regulates activation of ATF6 alpha during unfolded protein response

Activation of the ATF6 alpha signaling pathway is initiated by trafficking of ATF6 alpha 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 alpha are regulated and whether additional protein partners are required for its localization and processing remain unresolved. Here, we show that ER-resident oxidoreductase ERp18 associates with ATF6 alpha following ER stress and plays a key role in both trafficking and activation of ATF6 alpha. We find that ERp18 depletion attenuates the ATF6 alpha stress response. Paradoxically, ER stress accelerates trafficking of ATF6 alpha to the Golgi in ERp18-depleted cells. However, the translocated ATF6 alpha becomes aberrantly processed preventing release of the soluble transcription factor. Hence, we demonstrate that ERp18 monitors ATF6 alpha ER quality control to ensure optimal processing following trafficking to the Golgi.