Abstract
The endoplasmic reticulum (ER) plays important roles in protein synthesis and folding, and calcium storage. The volume of the ER and expression of its resident proteins are increased in response to nutrient stress. ER‐phagy, a selective form of autophagy, is involved in the degradation of the excess components of the ER to restore homeostasis. Six ER‐resident proteins have been identified as ER‐phagy receptors so far. In this study, we have identified CALCOCO1 as a novel ER‐phagy receptor for the degradation of the tubular ER in response to proteotoxic and nutrient stress. CALCOCO1 is a homomeric protein that binds directly to ATG8 proteins via LIR‐ and UDS‐interacting region (UIR) motifs acting co‐dependently. CALCOCO1‐mediated ER‐phagy requires interaction with VAMP‐associated proteins VAPA and VAPB on the ER membranes via a conserved FFAT‐like motif. Depletion of CALCOCO1 causes expansion of the ER and inefficient basal autophagy flux. Unlike the other ER‐phagy receptors, CALCOCO1 is peripherally associated with the ER. Therefore, we define CALCOCO1 as a soluble ER‐phagy receptor.
Highlights
Organelles are intracellular membrane-confined structures that carry out specialized functions important for cell function and survival
P62 and NDP52 were efficiently degraded in Torin 1-treated cells (Fig 4K). These results suggest that, while CALCOCO1 is required for basal autophagy, it is dispensable for bulk autophagy induced by either starvation or pharmacological inhibition of mTORC1
Co-expression of EGFP-CALCOCO1 with either Myc-VAPA or Myc-VAPB showed perinuclear co-localization (Fig 5E), suggesting association of CALCOCO1 and VAPs in cells. These results show that CALCOCO1 binds directly to endoplasmic reticulum (ER) integral membrane tethering proteins VAPA and VAPB via a FFAT-like motif
Summary
Organelles are intracellular membrane-confined structures that carry out specialized functions important for cell function and survival. The amount and vitality of each organelle is regulated depending on the energetic and functional needs of cells (Anding & Baehrecke, 2017). Surplus and damaged organelles are cleared through macro-autophagy ( autophagy) (Okamoto, 2014; Anding & Baehrecke, 2017), an evolutionary conserved process that delivers cytoplasmic materials for degradation in the lysosome (Mizushima & Komatsu, 2011; Ohsumi, 2014). Autophagy acts selectively in the degradation of excess components or toxic materials in the cell such as surplus or damaged organelles, protein aggregates, and invading pathogens (Johansen & Lamark, 2011, 2019; Stolz et al, 2014; Gatica et al, 2018; Kirkin, 2019). Autophagy is activated during stresses, such as starvation, to degrade cellular macromolecules in order to recycle nutrients and generate energy (Schroder, 2008; Ohsumi, 2014)
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