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Review
. 2022 Nov 1;14(11):a041254.
doi: 10.1101/cshperspect.a041254.

Lipid Transport from Endoplasmic Reticulum to Autophagic Membranes

Takuo Osawa  1 , Kazuaki Matoba  2 , Nobuo N Noda  2   3
Affiliations
Review

Lipid Transport from Endoplasmic Reticulum to Autophagic Membranes

Takuo Osawa et al. Cold Spring Harb Perspect Biol. .

Abstract

Autophagy is an intracellular degradation system involving de novo generation of autophagosomes, which function as a transporting vesicle of cytoplasmic components to lysosomes for degradation. Isolation membranes (IMs) or phagophores, the precursor membranes of autophagosomes, require millions of phospholipids to expand and transform into autophagosomes, with the endoplasmic reticulum (ER) being the primary lipid source. Recent advances in structural and biochemical studies of autophagy-related proteins have revealed their lipid transport activities: Atg2 at the interface between IM and ER possesses intermembrane lipid transfer activities, while Atg9 at IM and VMP1 and TMEM41B at ER possess lipid scrambling activities. In this review, we summarize recent advances in the establishment of the lipid transport activities of these proteins and their collaboration mechanisms for lipid transport between the ER and IM, and further discuss how unidirectional lipid transport from the ER to IM occurs during autophagosome formation.

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Figures

Figure 1.
Figure 1.
Schematic drawing of autophagosomal membrane expansion in budding yeast. The Atg2-Atg18 complex and Atg9 at the expanding edge of the isolation membrane (IM) contact the endoplasmic reticulum exit site (ERES) and are considered to be involved in lipid transfer from the ERES to the IM.
Figure 2.
Figure 2.
Structural basis of Atg2-mediated lipid transfer. (A) Crystal structure of phosphatidylethanolamine (PE)-bound SpAtg2NR (PDB 6A9J). Basic residues responsible for the membrane tethering activity of Atg2 are shown with red stick models. All structural models in this manuscript were prepared using PyMOL. (B) Capsule-like structures found in various lipid transfer proteins: SpAtg2NR, the amino-terminal region of Vps13 (Vps13NR; PDB 6CBC), cholesteryl ester transfer protein (CETP; PDB 2OBD), bactericidal permeability-increasing protein (BPI; PDB 1BP1), and extended synaptotagmin 2 (E-syt2; PDB 4P42). Monomers in capsule-like structures are colored in slate or salmon. Lipids bound to capsule-like structures are displayed as a sphere model. (C) AlphaFold structure of Atg2. (Left) Ribbon model of Atg2 whose domains are colored differently. (Middle and right) Outer and inner surface model of Atg2 in which hydrophobicity is shown in Kyte–Doolittle scale. The most hydrophobic region is colored in orange-red. (D) Fitting of the AlphaFold structure of ATG2A to the electron microscopy (EM) density map of the ATG2A-WIPI4 complex (EMD-8899). (E) Cryo-EM density map of the amino-terminal fragment of Chaetomium thermophilum VPS13 (EMD-21113).
Figure 3.
Figure 3.
Structural basis of Atg9-mediated lipid scrambling. (A) Ribbon model of fission yeast Atg9 (PDB 7D0I). One protomer is colored orange, whereas the other two protomers within a trimer are colored light and dark gray, respectively. (TM) Transmembrane helices. (B) Schematic drawing of Atg9 trimer. (C) Lipids and detergents bound to the lateral pore (LP) and vertical pore (VP) of Atg9/ATG9A. (Left) Lipids bound to the outer side of VP and LP of human ATG9A (PDB 6WQZ). (Middle) LMNG bound to the LP of human ATG9A (PDB 7JLP). (Right) LMNG bound to the LP of fission yeast Atg9. (D) Various-sized VPs observed at the center of the Atg9/ATG9A trimers.
Figure 4.
Figure 4.
AlphaFold structure of TMEM41B. (Left) Two reentrant loops are colored red. (Right) Red and blue shading represents negatively and positively charged regions, respectively. TM indicates predicted transmembrane region.
Figure 5.
Figure 5.
Mechanisms of the ER-to-IM phospholipid transfer (left) and LPS transport (right). Regions responsible for similar functions are displayed in the same colors. Arrows indicate the lipid flow. For clarity, peptidoglycan layers are not shown in LPS transport. (G3P) Glycerol 3-phosphate, (FFA) free fatty acid, (Pi) inorganic phosphate, (PPi) inorganic pyrophosphate.
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