The endoplasmic reticulum (ER)-associated degradation (ERAD) pathway is activated by the unfolded protein response (UPR) and is vital in removing overloaded proteins to ameliorate ER stress.

Autophagy is a noncanonical ERAD pathway degrading cellular contents in the lysosome and has been reported to be triggered upon ER stress to eliminate excess proteins and maintain protein homeostasis. However, the signaling pathways that couple ER stress to autophagy are not completely understood.

Based on the previous findings that berberine relieves hepatic steatosis and maintains energy balance by activating autophagy and FGF21 signaling, a team of researchers led by Prof. LI Yu at Shanghai Institute of Nutrition and Health of Chinese Academy of Sciences discoverd that a quality-control ER chaperon, Calreticulin, is induced under ER stress and triggers autophagy via interacting with MAP1LC3 (LC3).

This axis promotes the degradation of aberrantly folded proteins and alleviation of ER stress via a negative feedback loop.

In the study, researchers confirmed the upregulation of Calreticulin under ER stress both in vivo and in vitro. The ER stress-ameliorating role of Calreticulin was revealed through genetic overexpression and shRNA-mediated stably knockdown experiments.

They then examined the levels of autophagy in the above contexts and verified the role of Calreticulin in promoting autophagy.

Furthermore, researchers characterized the interaction between Calreticulin and the autophagic protein LC3 and identified its interaction region. In vitro experiments indicated that this association is indispensable for the beneficial role of Calreticulin in alleviating ER stress via autophagy.

The results provided a potential therapeutic strategy for hyperactive ER stress and its related disorders.

This study was published online in Journal of Biological Chemistry. It was funded by the grants from Ministry of Science and Technology of China, National Natural Science Foundation of China, Chinese Academy of Sciences, and K. C. Wong Education Foundation.