Zn²⁺-dependent functional switching of ERp18, an ER-resident thioredoxin-like protein

ERp18 is an endoplasmic reticulum (ER)-resident thioredoxin (Trx) family protein, similar to cytosolic Trx1. The Trx-like domain occupies a major portion of the whole ERp18 structure, which is postulated to be an ER paralog of cytosolic Trx1. Here, we elucidate that zinc ion (Zn²⁺) binds ERp18 through its catalytic motif, triggering oligomerization of ERp18 from a monomer to a trimer. While the monomeric ERp18 has disulfide oxidoreductase activity, the trimeric ERp18 acquires scavenger activity for hydrogen peroxide (H₂O₂) in the ER. Depletion of ERp18 thus causes the accumulation of H₂O₂, which is produced during the oxidative folding of nascent polypeptides in the ER. ERp18 knockdown in C. elegans without Prx4 and GPx7/8, both of which are also known to have H₂O₂ scavenging activity in the ER, shortened the lifespan, suggesting that ERp18 may form a primitive and essential H₂O₂ scavenging system for the maintenance of redox homeostasis in the ER.