Cell Biology
The ER-localized Ca2+-binding protein calreticulin couples ER stress to autophagy by associating with microtubule-associated protein 1A/1B light chain 3

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Autophagy is of key importance for eliminating aggregated proteins during the maintenance of cellular proteostasis in response to endoplasmic reticulum (ER) stress. However, the upstream signaling that mediates autophagy activation in response to ER stress is incompletely understood. In this study, in vivo and in vitro approaches were utilized that include gain- and loss-of-function assays and mouse livers and human cell lines with tunicamycin-induced pharmacological ER stress. We report that calreticulin, a quality control chaperone that binds to misfolded glycoproteins for refolding in the ER, is induced under ER stress. Calreticulin overexpression stimulated the formation of autophagosomes and increased autophagic flux. Interestingly, calreticulin was sufficient for attenuating ER stress in tunicamycin- or thapsigargin-treated HeLa cells, whereas lentivirus-mediated shRNA calreticulin knockdown exacerbated ER stress. Mechanistically, we noted that calreticulin induces autophagy by interacting with microtubule-associated protein 1A/1B-light chain 3 (LC3). Confocal microscopy revealed that the colocalization of calreticulin and LC3 at the autophagosome was enhanced under ER stress conditions. Importantly, a conserved LC3-interacting region was necessary for calreticulin-mediated stimulation of autophagy and for reducing ER stress. These findings indicate a calreticulin-based mechanism that couples ER stress to autophagy activation, which, in turn, attenuates cellular stress, likely by alleviating the formation of aberrantly folded proteins. Pharmacological or genetic approaches that activate calreticulin–autophagy signaling may have potential for managing ER stress and related cellular disorders.

endoplasmic reticulum stress (ER stress)
autophagy
unfolded protein response (UPR)
chaperone
proteostasis
protein misfolding
calreticulin
LC3
LC3-interacting region (LIR motif)

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This work was supported by National Key R&D Program of China Grant 2017YFC0909601, National Natural Science Foundation of China Grants 31471129 and 31671224, Chinese Academy of Sciences Grant ZDBS-SSW-DQC-02, and the K. C. Wong Education Foundation (to Y. Li) The authors declare that they have no conflicts of interest with the contents of this article.

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Both authors contributed equally to this work.