Activation of the UPR sensor ATF6α is regulated by its redox-dependent dimerization and ER retention by ERp18

The unfolded protein response (UPR) maintains cellular proteostasis during stress by activating sensors located to the endoplasmic reticulum (ER) membrane. A major sensor for this response, ATF6 alpha, is activated by release from ER retention and trafficking to the Golgi, where it is cleaved to generate a bZIP transactivator to initiate a transcriptional response. The reduction of a disulfide in monomeric ATF6 alpha is thought to be necessary for release from retention, trafficking, and proteolysis. Here we show that, following ER stress, ATF6 alpha undergoes a redox switch to form a disulfide bonded dimer, which traffics to the Golgi for cleavage by the S1P protease. Additionally, we find that overexpression of ERp18 attenuates dimer formation thereby limiting Golgi trafficking. Our results provide mechanistic insight into activation of the ATF6 alpha pathway, revealing an unexpected role for redox-dependent oligomerization prior to Golgi trafficking.

Automated summary

The unfolded protein response (UPR) regulates cellular proteostasis by activating and trafficking the ATF6 alpha sensor. After ER stress, ATF6 alpha undergoes a redox switch to form a disulfide bonded dimer, which is then transported to the Golgi for cleavage. Overexpression of ERp18 affects dimer formation and limits Golgi trafficking.