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bioRxiv · 10.1101/2023.06.14.545011

A KDELR-mediated ER retrieval system guides the signaling pathways of UPR and AMPK to maintain cellular homeostasis

Zhu, M.·Fang, Z.·Wu, Y.·Dong, F.·Wang, Y.·Zheng, F.·Ma, X.·Ma, S.·He, J.·Hill, D. L.·Liu, X.·Yao, X.·Fu, C.
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Abstract

KDELR (Erd2 in yeasts) mediates the retrieval of ER-resident proteins from the Golgi apparatus, yet how the KDELR-mediated ER retrieval system is involved in regulating cellular homeostasis has been unclear. Here we report that the loss of the Erd2-mediated ER retrieval system induces the unfolded protein response (UPR) and increases mitochondrial respiration and reactive oxygen species (ROS) in an UPR-dependent manner. Moreover, transcriptomic analysis revealed that expression of the genes involved in mitochondrial respiration and the tricarboxylic acid cycle is enhanced in an UPR-dependent manner in cells lacking Erd2. In cells lacking Erd2, the enhancement of mitochondrial respiration and ROS is required for maintaining cell viability. The loss of the Erd2-mediated ER retrieval system also activates AMPK, and consequently derepresses carbon catabolite repression. Hence, our work establishes a role of the KDELR/Erd2-mediated ER retrieval system in guiding the signalling pathways of AMPK and UPR and underscores the crucial role of the KDELR/Erd2-mediated ER retrieval system in the maintenance of cellular homeostasis.

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Zhu, M., Fang, Z., Wu, Y., Dong, F., Wang, Y., Zheng, F., Ma, X., Ma, S., He, J., Hill, D. L., Liu, X., Yao, X., Fu, C.. 2023-06-15. A KDELR-mediated ER retrieval system guides the signaling pathways of UPR and AMPK to maintain cellular homeostasis. https://doi.org/10.1101/2023.06.14.545011

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