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Review
. 2021 Mar 1;220(3):e202012058.
doi: 10.1083/jcb.202012058.

Mechanisms of nonvesicular lipid transport

Karin M Reinisch  1 , William A Prinz  2
Affiliations
Review

Mechanisms of nonvesicular lipid transport

Karin M Reinisch et al. J Cell Biol. .

Abstract

We have long known that lipids traffic between cellular membranes via vesicles but have only recently appreciated the role of nonvesicular lipid transport. Nonvesicular transport can be high volume, supporting biogenesis of rapidly expanding membranes, or more targeted and precise, allowing cells to rapidly alter levels of specific lipids in membranes. Most such transport probably occurs at membrane contact sites, where organelles are closely apposed, and requires lipid transport proteins (LTPs), which solubilize lipids to shield them from the aqueous phase during their transport between membranes. Some LTPs are cup like and shuttle lipid monomers between membranes. Others form conduits allowing lipid flow between membranes. This review describes what we know about nonvesicular lipid transfer mechanisms while also identifying many remaining unknowns: How do LTPs facilitate lipid movement from and into membranes, do LTPs require accessory proteins for efficient transfer in vivo, and how is directionality of transport determined?

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Figures

Figure 1.
Figure 1.
Functions of nonvesicular lipid transport. (A) High-volume lipid transport required for membrane expansion (bulk transport). Shown for growth of an autophagosome and also necessary for biogenesis of mitochondria and chloroplasts. (B) Types of lower-volume lipid transport. Representative examples of three functions are shown. One is to support lipid-based signaling (left). The protein Nir2 transfers PI from the ER to the plasma membrane, where it is converted to PI4P by the enzyme phosphatidylinositol 4-kinase-α (PI4KA). PI4P can removed from the plasma membrane by ORP5 or ORP8, which bring it to the ER, where it is hydrolyzed by the phosphatidylinositide phosphatase, Sac1. Lipid transport can also regulate the levels of a specific lipid. For example, OSBP uses counter-exchange transport to enrich cholesterol in the Golgi membrane (center). Lipid transport can also support membrane domain formation. For example, Lam6/Ltc1 brings the sterol, ergosterol, to the vacuole in S. cerevisiae and supports membrane domain formation there (right; domain in red).
Figure 2.
Figure 2.
Lipid transport machinery. (A) Schematic of a shuttling LTP (left) and a bridge-like LTP (right). A shuttling LTP (blue) extracts lipid monomers from one bilayer and then diffuses to a second bilayer and delivers the lipid. Bridge-like LTPs (light blue) form conduits that allow lipid molecules to flow between membranes. (B) Cup-like lipid transport modules with lipid bound. Osh4 can bind either sterol or PI4P (magenta) in the same pocket, with slight rearrangements in the lids (yellow). Osh4 is shown in different orientations. The StART-domain of CERT is shown with ceramide (magenta) bound. Protein Data Bank accession nos. are indicated: 1ZHZ, 3SPW, 2E3O, 6CBC, 6A9J, 5TV4, and 6MIT. (C) Bridge-like lipid transporters. From left to right: Intact VPS13 structure at ∼30-Å resolution by negative stain EM (De et al., 2017; courtesy of Y. Skiniotis, Stanford School of Medicine, Stanford, CA); cryo-EM structure of the N-terminal 160 kD of VPS13 showing it forms a tunnel (EMD-21113); ribbons representations of the VPS13 and ATG2 N-terminal fragments, showing they have the same fold; and ∼18-Å resolution cryo-EM structure of intact ATG2. (D) The LPS transport system in the inner membrane of E. coli, showing the flippase MsbA, which flips LPS from the inner to the outer leaflet of the membrane, and part of the transporter, which features an integral membrane portion that helps to load lipid into the bridge-like portion (indicated). ATPase domains in MsbA and in the LPS transporter are highlighted (light green and light blue).
Figure 3.
Figure 3.
Examples of five mechanisms of directional transport. (A) Lipid consumption–driven lipid transport. Ceramide is transported by CERT from the ER to the Golgi, where it is converted to sphingomyelin (SM) and other complex sphingolipids and cannot be returned to the ER by CERT. (B) Lipid domain formation can drive lipid transport when a lipid becomes associated with a domain in one of the two membranes. Lam6/Ltc1 brings the sterol, ergosterol, to the vacuole in S. cerevisiae, and membrane domain formation probably drives the accumulation of ergosterol (domain in red). (C) Lipid synthesis at MCSs can drive lipid transport. PS synthesis at ER–mitochondria contact sites in S. cerevisiae promotes PS transport to mitochondria. (D) ATP consumption drives LPS transport from the inner to the outer membrane of E. coli. (E) Counter-exchange transport using the difference in PIP concentration in two membranes to drive the transport of a second lipid. OSBP uses counter-exchange transport to enrich cholesterol in the Golgi membrane.
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