Coupling of cargo to the autophagy receptor is a critical step in ER-phagy
- Shuliang Chen
- Subhrajit Banerjee
- Dongmei Liu
- Kamal Kumar
- Christopher J. Obara
- Peter Novick
- William A. Prinz
- Susan Ferro-Novick
2026-06-12
During cell stress, endoplasmic reticulum autophagy (ER-phagy) receptors remodel the ER by sequestering membrane proteins (cargo) into autophagosomes for degradation. The conserved ER-phagy receptor, Atg40, contains a motif that binds to Atg8 and a reticulon homology domain that is needed for vacuolar/lysosomal delivery. Cargo capture, however, requires the Atg40 binding partner Lst1/SEC24C. To address whether lipids regulate cargo capture during ER-phagy, we analyzed autophagy in neutral lipid–deficient cells. Unexpectedly, we found that Atg40 was delivered to the vacuole in autophagosomes without Lst1/SEC24C or cargo in mutant cells. Lipidomic analysis revealed changes in the ratio of phosphatidylethanolamine to phosphatidylcholine in the neutral lipid–deficient cells that are predicted to alter ER membrane bendability. Our findings imply that phospholipids control cargo sequestration by regulating receptor-cargo coupling at autophagic sites.