Proteomics

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


ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Rattus Norvegicus (rat) Homo Sapiens (human)

SUBMITTER: Giorgia Di Lorenzo  

LAB HEAD: Carmine Settembre

PROVIDER: PXD030451 | Pride | 2022-10-14

REPOSITORIES: Pride

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Selective degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is initiated by ER-phagy receptors, which facilitate the incorporation of ER fragments into autophagosomes. FAM134 reticulon family proteins (FAM134A, FAM134B, and FAM134C) are ER-phagy receptors with structural similarities and nonredundant functions. Whether they respond differentially to the stimulation of ER-phagy is unknown. Here, we describe an activation mechanism unique to FAM134C during starvation. In fed c  ...[more]

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