2. Academic Validation
  3. Regulation of the endoplasmic reticulum stress sensor ATF6α through multiple oxidoreductases in the ER

Regulation of the endoplasmic reticulum stress sensor ATF6α through multiple oxidoreductases in the ER

  • iScience. 2026 Jun 4;29(6):116290. doi: 10.1016/j.isci.2026.116290.
Shota Wada 1,  Kaiku Uegaki 2,  Kazuhiro Nagata 1 3 4 5,  Ryo Ushioda 1 4 5
Affiliations

Affiliations

  • 1 Department of Frontier Life Sciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan.
  • 2 Howard Hughes Medical Institute and Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
  • 3 JT Biohistory Research Hall, Murasaki Town 1-1, Takatsuki City, Osaka 569-1125, Japan.
  • 4 Institute for Protein Dynamics, Kyoto Sangyo University, Kyoto 605-8555, Japan.
  • 5 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Saitama 332-0012, Japan.
PMID: 42305590 DOI: 10.1016/j.isci.2026.116290
Abstract

The unfolded protein response (UPR) maintains cellular homeostasis during ER stress. In this process, activating transcription factor 6α (ATF6α) is activated through several multi-step processes, including transport to the Golgi apparatus, and plays an important role as a UPR sensor. Disulfide bond-mediated dimerization of ATF6α contributes to efficient transport to the Golgi apparatus. However, this regulatory mechanism remains unclear. Here, we show that ER-resident oxidoreductases, including ERdj5 and PDIR, promote C467 dimerization, whereas ERp18 inhibits this process. In particular, ERdj5 facilitates C467 dimerization via Trx2 and reduces C618 dimerization via Trx3, supporting ATF6α activation. Furthermore, ATF6α dimerization stabilizes its structure and prevents its degradation by ER-associated degradation (ERAD). Our findings reveal that multiple oxidoreductases participate in the regulation of ATF6α activation during ER stress.

Keywords

molecular interaction; molecular network; protein.

Figures
Products