The core morning clock component CCA1 enhances UPR target gene expression to facilitate ER stress recovery

Abstract

The endoplasmic reticulum (ER) is a cellular organelle responsible for protein synthesis and folding. When its protein folding capacity is exceeded, unfolded or misfolded proteins accumulate, causing ER stress and triggering the unfolded protein response (UPR) to restore ER proteostasis. Although UPR gene expression in plants follows a diel cycle, the mechanisms by which the circadian clock regulates these genes remain unclear. Here, we demonstrate that sensitivity to ER stress in root growth exhibits time-of-day phases and that the circadian clock regulates UPR target gene expression during ER stress. Notably, mutations in the core morning clock component CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) impair ER stress recovery. CCA1 forms a complex with the UPR modulator basic leucine zipper 28 (bZIP28) and acts as an upstream regulator of ER stress recovery. Upon ER stress, CCA1 is stabilized and associates with bZIP28 at the ER stress response element within the BiP3 promoter, enhancing the ER stress response. Thus, CCA1 and bZIP28 coordinate a time-dependent adaptive response to ER stress to maintain ER proteostasis. Our results suggest that the circadian clock primes the timing and levels of ER chaperone expression to enhance ER stress tolerance. © 2025 The Author(s)