An mTORC1-CK2 axis controls starvation induced ER-phagy via FAM134C

The degradation of endoplasmic reticulum (ER) via selective autophagy is driven by the ER-phagy receptors that facilitate the incorporation of ER-fragments into nascent autophagosomes. How these receptors are regulated, in response to ER-phagy-inducing stimuluses, is largely unknown. Here we propose that starvation, as well as mTOR inhibition, triggers ER-phagy primarily through the activation of the ER-phagy receptor FAM134C. In physiological, nutrient reach, conditions FAM134C is phosphorylated by the Casein kinase 2 (CK2) protein at specific residues negatively affecting FAM134C interaction with the LC3 proteins, thereby preventing ER-phagy. Pharmacological or starvation-induced mTORC1 inhibition limits phosphorylation of FAM134C by CK2, hence promoting FAM134C activation and ER-phagy. Moreover, inhibition of CK2 or the expression of a phospho-mutant FAM134C protein is sufficient to stimulate ER-phagy. Conversely, starvation induced ER-phagy is inhibited in cells and mice that lack FAM134C or expressing a phospho-mimetic FAM134C protein. Overall, these data describe a new mechanism regulating ER-phagy and provides an example of cargo selectivity mechanism during starvation induced autophagy.